U.S. patent application number 12/828855 was filed with the patent office on 2012-03-08 for azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof.
This patent application is currently assigned to ALBANY MOLECULAR RESEARCH, INC.. Invention is credited to Emily Elizabeth FREEMAN, Peter R. GUZZO, Mark HADDEN, Alan John HENDERSON, Matthew David SURMAN.
Application Number | 20120058939 12/828855 |
Document ID | / |
Family ID | 43411457 |
Filed Date | 2012-03-08 |
United States Patent
Application |
20120058939 |
Kind Code |
A9 |
GUZZO; Peter R. ; et
al. |
March 8, 2012 |
AZABICYCLOALKANE-INDOLE AND AZABICYCLOALKANE-PYRROLO-PYRIDINE MCH-1
ANTAGONISTS, METHODS OF MAKING, AND USE THEREOF
Abstract
Novel MCH-1 receptor antagonists are disclosed. These compounds
are used in the treatment of various disorders, including obesity,
anxiety, depression, non-alcoholic fatty liver disease, and
psychiatric disorders. Methods of making these compounds are also
described in the present invention.
Inventors: |
GUZZO; Peter R.; (Niskayuna,
NY) ; SURMAN; Matthew David; (Albany, NY) ;
HENDERSON; Alan John; (Albany, NY) ; HADDEN;
Mark; (Albany, NY) ; FREEMAN; Emily Elizabeth;
(Guilderland, NY) |
Assignee: |
ALBANY MOLECULAR RESEARCH,
INC.
Albany
NY
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20110003737 A1 |
January 6, 2011 |
|
|
Family ID: |
43411457 |
Appl. No.: |
12/828855 |
Filed: |
July 1, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61222440 |
Jul 1, 2009 |
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61329428 |
Apr 29, 2010 |
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Current U.S.
Class: |
514/5.3 ;
514/171; 514/252.03; 514/253.02; 514/254.08; 514/256; 514/286;
514/333; 514/338; 514/5.8; 514/8.4; 514/9.7; 544/238; 544/333;
544/361; 544/372; 546/256; 546/276.7; 546/63 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
1/16 20180101; A61P 25/24 20180101; A61P 25/28 20180101; A61P 25/08
20180101; C07D 471/22 20130101; A61P 25/22 20180101; A61P 1/08
20180101; A61P 25/30 20180101; A61P 25/00 20180101; A61P 25/16
20180101 |
Class at
Publication: |
514/5.3 ;
546/276.7; 544/238; 546/256; 544/333; 546/63; 544/372; 544/361;
514/338; 514/252.03; 514/333; 514/256; 514/286; 514/254.08;
514/253.02; 514/5.8; 514/9.7; 514/171; 514/8.4 |
International
Class: |
A61K 38/22 20060101
A61K038/22; C07D 471/08 20060101 C07D471/08; C07D 471/18 20060101
C07D471/18; A61K 31/4439 20060101 A61K031/4439; A61K 31/501
20060101 A61K031/501; A61K 31/444 20060101 A61K031/444; A61K 31/506
20060101 A61K031/506; A61K 31/437 20060101 A61K031/437; A61K 31/497
20060101 A61K031/497; A61K 31/5685 20060101 A61K031/5685; A61K
38/18 20060101 A61K038/18; A61P 3/04 20060101 A61P003/04; A61P
25/22 20060101 A61P025/22; A61P 25/24 20060101 A61P025/24; A61P
1/16 20060101 A61P001/16; A61P 1/08 20060101 A61P001/08; A61P 25/28
20060101 A61P025/28; A61P 25/16 20060101 A61P025/16; A61P 25/30
20060101 A61P025/30; A61P 25/00 20060101 A61P025/00; A61P 25/08
20060101 A61P025/08; C07D 487/04 20060101 C07D487/04 |
Claims
1. A compound of formula I: ##STR00211## wherein R.sup.1 is
selected from the group consisting of H, --S(O).sub.qR.sup.6,
--C(O)R.sup.6, --C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, and
heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, and heteroaryl is
optionally substituted with from 1 to 3 substituents independently
selected at each occurrence thereof from C.sub.1-C.sub.3 alkyl,
halogen, --CN, --OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is
optionally substituted 1-3 times with halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.2 is selected from the
group consisting of H, --S(O).sub.qR.sup.6, --C(O)R.sup.6,
--C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and
heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl
is optionally substituted with from 1 to 3 substituents
independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.3 is independently selected at each
location from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, --CN, C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.4 is selected from the
group consisting of H, halogen, --OR.sup.5, --NR.sup.5R.sup.6,
--NR.sup.5C(O)R.sup.6, --NR.sup.5C(O).sub.2R.sup.6,
--NR.sup.6C(O)NR.sup.6R.sup.7, --S(O).sub.qR.sup.6, --CN,
--C(O)R.sup.6, --C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl is optionally substituted with from 1 to 3
substituents independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.5 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
--C(O)R.sup.7, phenyl, or benzyl, wherein phenyl or benzyl is
optionally substituted 1 to 3 times with halogen, cyano,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.6 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
phenyl, or benzyl, wherein phenyl or benzyl is optionally
substituted 1 to 3 times with halogen, cyano, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 alkoxy;
R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
phenyl; R.sup.8 and R.sup.9 are each independently H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, --C(O)R.sup.7, phenyl, or benzyl, wherein phenyl
or benzyl is optionally substituted from 1 to 3 times with a
substituent selected independently at each occurrence thereof from
the group consisting of halogen, cyano, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 alkoxy; R.sup.10 is
selected from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, --CN, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; X is CR.sup.10,
C(R.sup.10).sub.2, N, or NR.sup.10; Y is CR.sup.10, C, or N; Z is
C, CH, or N; L is --(CH.sub.2).sub.p--O--, --(CH.sub.2).sub.p--,
--CH.dbd.CH--, or a bond; B is aryl, heteroaryl, heterocyclyl, or
cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or
cycloalkyl is optionally substituted with from 1 to 3 substituents
selected from the group consisting of H, alkoxy, --S-alkyl,
optionally substituted C.sub.1-C.sub.6 alkyl, halogen, --CF.sub.3,
and --CN; n is 1 or 2; m is 0, 1, 2, or 3; p is from 1 to 4; q is
0, 1, or 2; and represents an optional double bond, or an oxide
thereof, a pharmaceutically acceptable salt thereof, a solvate
thereof, or prodrug thereof.
2. The compound according to claim 1, wherein R.sup.1 is H.
3. The compound according to claim 1, wherein R.sup.1 is alkyl.
4. The compound according to claim 1, wherein R.sup.2 is H.
5. The compound according to claim 1, wherein X is C.
6. The compound according to claim 1, wherein X is N.
7. The compound according to claim 1, wherein L is a bond.
8. The compound according to claim 1, wherein L is
--CH.sub.2--O--.
9. The compound according to claim 1, wherein L is
--CH.sub.2--CH.sub.2--.
10. The compound according to claim 1, wherein B is aryl.
11. The compound according to claim 10, wherein B is phenyl.
12. The compound according to claim 1, wherein B is heteroaryl.
13. The compound according to claim 12, wherein B is pyridinyl.
14. The compound according to claim 13, wherein B is
pyridin-2-yl.
15. The compound according to claim 13, wherein B is
pyridin-3-yl.
16. The compound according to claim 12, wherein B is
pyridazinyl.
17. The compound according to claim 16, wherein B is
pyridazin-3-yl.
18. The compound according to claim 12, wherein B is
pyrimidinyl.
19. The compound according to claim 18, wherein B is
pyrimidin-5-yl.
20. The compound according to claim 1, wherein B is
unsubstituted.
21. The compound according to claim 1, wherein B is substituted
with one substituent selected from the group consisting of methyl,
trifluoromethyl, chloro and fluoro.
22. The compound according to claim 1, wherein B is selected from
the group consisting of phenyl, 5-(trifluoromethyl)pyridin-2-yl,
5-fluoropyridin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl,
6-(trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyrimidin-5-yl,
6-methylpyridin-3-yl, pyridin-2-yl, 2,4-difluorophenyl,
4-chlorophenyl, 4-chloro-2-fluorophenyl, 2,4-dichlorophenyl, and
4-(trifluoromethyl)phenyl.
23. The compound according to claim 1, wherein the compound has the
formula: ##STR00212##
24. The compound according to claim 1, wherein the compound is
selected from the group consisting of ##STR00213## ##STR00214##
##STR00215##
25. The compound according to claim 1, wherein the compound is
selected from the group consisting of ##STR00216## ##STR00217##
##STR00218## ##STR00219## ##STR00220##
26. The compound according to claim 1, wherein the compound is
selected from the group consisting of ##STR00221## ##STR00222##
27. The compound according to claim 1, wherein the compound is an
HCl salt.
28. A pharmaceutical composition comprising a therapeutically
effective amount of the compound according to claim 1 and a
pharmaceutically acceptable carrier.
29. A method of treating a disease or condition which is
susceptible to treatment with a MHC-1 receptor antagonist
comprising: selecting a patient with a disease or condition which
is susceptible to treatment with a MCH-1 antagonist, and
administering to the patient a therapeutically effective amount of
a compound of claim 1 or a pharmaceutically acceptable salt
thereof.
30. The method according to claim 29, wherein the disease or
condition is selected from the group consisting of obesity, general
anxiety disorders, social phobias, vertigo, obsessive-compulsive
disorders, panic disorders, post-traumatic stress disorders,
Parkinson's Disease Psychosis, schizophrenia, cognitive decline and
defects in schizophrenia, presenile dementias, Alzheimer's Disease,
psychological disorders, depression, substance abuse disorders,
dementia associated with neurodegenerative disease, cognition
deficits, and epilepsy.
31. The method according to claim 29 further comprising:
administering to the patient a therapeutically effective amount of
a therapeutic adjunct.
32. The method according to claim 31, wherein the therapeutic
adjunct is selected from the group consisting of
phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a
cholecystokinin-A agonist, a monoamine reuptake inhibitor, a
sympathomimetic agent, a serotonergic agent, a dopamine agonist, a
melanocyte-stimulating hormone receptor agonist or mimetic, a
melanocyte-stimulating hormone analog, a cannabinoid receptor
antagonist or inverse agonist, a melanin concentrating hormone
receptor antagonist, a serotonin 5-HT.sub.6 receptor antagonist, a
serotonin 5-HT.sub.2C receptor agonist, leptin, a leptin analog, a
leptin receptor agonist, amylin peptide, an amylin analog, an
amylin receptor agonist, a neuropeptide Y receptor modulator, a
galanin antagonist, a GI lipase inhibitor or decreaser, a bombesin
agonist, dehydroepiandrosterone or analogs thereof, a
glucocorticoid receptor agonist, a glucocorticoid receptor
antagonist, an orexin receptor antagonist, an urocortin binding
protein antagonist, an agonist of the glucagon-like peptide-1
receptor, a ciliary neurotrophic factor, an allosteric modulator of
the GABA.sub.A receptor, a serotonin 5-HT.sub.1A receptor partial
agonist, a selective serotonin reuptake inhibitor, a
serotonin-norepinephrine reuptake inhibitor, a monoamine
neurotransmitter reuptake inhibitor of tricyclic antidepressant
class, a combined serotonin reuptake inhibitor and 5-HT.sub.2C
antagonist, an H.sub.1 receptor antagonist, a noradrenergic and
specific serotonergic antidepressant, a norepinephrine reuptake
inhibitor, a norepinephrine-dopamine reuptake inhibitor, a
monoamine oxidase inhibitor, an AMP-activated protein kinase
agonist, a peroxisome proliferator-activated receptor gamma
activator, a HMG-CoA reductase inhibitor, a PDE4 inhibitor, and
combinations thereof.
33. A method of treating obesity in a subject in need of weight
loss comprising: selecting a patient in need of weight loss, and
administering to the patient a therapeutically effective amount of
a compound of claim 1 or a pharmaceutically acceptable salt
thereof.
34. The method according to claim 33 further comprising:
administering to the patient a therapeutically effective amount of
an anti-obesity adjunct.
35. The method according to claim 34, wherein the anti-obesity
adjunct is selected from the group consisting of
phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a
cholecystokinin-A agonist, a monoamine reuptake inhibitor, a
sympathomimetic agent, a serotonergic agent, a dopamine agonist, a
melanocyte-stimulating hormone receptor agonist or mimetic, a
melanocyte-stimulating hormone analog, a cannabinoid receptor
antagonist or inverse agonist, a melanin concentrating hormone
receptor antagonist, a serotonin 5-HT.sub.6 receptor antagonist, a
serotonin 5-HT.sub.2C receptor agonist, leptin, a leptin analog, a
leptin receptor agonist, amylin peptide, an amylin analog, an
amylin receptor agonist, a neuropeptide Y receptor modulator, a
galanin antagonist, a GI lipase inhibitor or decreaser, a bombesin
agonist, dehydroepiandrosterone or analogs thereof, a
glucocorticoid receptor agonist, a glucocorticoid receptor
antagonist, an orexin receptor antagonist, an urocortin binding
protein antagonist, an agonist of the glucagon-like peptide-1
receptor, a ciliary neurotrophic factor, and combinations
thereof.
36. A method of treating obesity in a subject who has experienced
weight loss comprising: selecting a patient who has experienced
weight loss, and administering to the patient a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt thereof.
37. A method of treating anxiety comprising: selecting a patient
with anxiety, and administering to the patient a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt thereof.
38. The method according to claim 37 further comprising:
administering to the patient a therapeutically effective amount of
a anti-anxiety adjunct.
39. The method according to claim 38, wherein the anti-anxiety
adjunct is selected from the group consisting of an allosteric
modulator of the GABA.sub.A receptor, a serotonin 5-HT.sub.1A
receptor partial agonist, a selective serotonin reuptake inhibitor,
a serotonin-norepinephrine reuptake inhibitor, a monoamine
neurotransmitter reuptake inhibitor of tricyclic antidepressant
class, a combined serotonin reuptake inhibitor and 5-HT.sub.2C
antagonist, an H.sub.1 receptor antagonist, and combinations
thereof.
40. A method of treating depression comprising: selecting a patient
with depression, and administering to the patient a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt thereof.
41. The method according to claim 40 further comprising:
administering to the patient a therapeutically effective amount of
an anti-depression adjunct.
42. The method according to claim 41, wherein the anti-depression
adjunct is selected from the group consisting of a serotonin
5-HT.sub.1A receptor partial agonist, a selective serotonin
reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor,
a monoamine neurotransmitter reuptake inhibitor of tricyclic
antidepressant class, a combined serotonin reuptake inhibitor and
5-HT.sub.2C antagonist, a noradrenergic and specific serotonergic
antidepressant, a norepinephrine reuptake inhibitor, a
norepinephrine-dopamine reuptake inhibitor, a monoamine oxidase
inhibitor, and combinations thereof.
43. A method of treating non-alcoholic fatty liver disease
comprising: selecting a patient who has non-alcoholic fatty liver
disease, and administering to the patient a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt thereof.
44. The method according to claim 43 further comprising:
administering to the patient a therapeutically effective amount of
an anti-non-alcoholic fatty liver disease adjunct.
45. The method according to claim 44, wherein the
anti-non-alcoholic fatty liver disease adjunct is selected from the
group consisting of an AMP-activated protein kinase agonist, a
peroxisome proliferator-activated receptor gamma activator, a
HMG-CoA reductase inhibitor, a PDE4 inhibitor, and combinations
thereof.
46. A process for preparation of a product compound of formula I:
##STR00223## wherein R.sup.1 is selected from the group consisting
of H, --S(O).sub.qR.sup.6, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.2 is selected from the
group consisting of H, --S(O)R.sup.6, --C(O)R.sup.6,
--C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and
heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl
is optionally substituted with from 1 to 3 substituents
independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.3 is independently selected at each
location from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, --CN, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.4 is selected from the
group consisting of H, halogen, --OR.sup.5, --NR.sup.5R.sup.6,
--NR.sup.5C(O)R.sup.6, --NR.sup.5C(O).sub.2R.sup.6,
--NR.sup.6C(O)NR.sup.6R.sup.7, --S(O).sub.qR.sup.6, --CN,
--C(O)R.sup.6, --C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl is optionally substituted with from 1 to 3
substituents independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.5 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
--C(O)R.sup.7, phenyl, or benzyl, wherein phenyl or benzyl is
optionally substituted 1 to 3 times with halogen, cyano,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.6 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
phenyl, or benzyl, wherein phenyl or benzyl is optionally
substituted 1 to 3 times with halogen, cyano, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 alkoxy;
R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
phenyl; R.sup.8 and R.sup.9 are each independently H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, --C(O)R.sup.7, phenyl, or benzyl, wherein phenyl
or benzyl is optionally substituted from 1 to 3 times with a
substituent selected independently at each occurrence thereof from
the group consisting of halogen, cyano, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 alkoxy; R.sup.10 is
selected from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, --CN, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; X is CR.sup.10,
C(R.sup.10).sub.2, N, or NR.sup.10; Y is CR.sup.10, C, or N; Z is
C, CH, or N; L is --(CH.sub.2).sub.p--O--, --(CH.sub.2).sub.p--,
--CH.dbd.CH--, or a bond; B is aryl, heteroaryl, heterocyclyl, or
cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or
cycloalkyl is optionally substituted with from 1 to 3 substituents
selected from the group consisting of H, alkoxy, --S-alkyl,
optionally substituted C.sub.1-C.sub.6 alkyl, halogen, --CF.sub.3,
and --CN; n is 1 or 2; m is 0, 1, 2, or 3; p is from 1 to 4; q is
0, 1, or 2; and represents an optional double bond, said process
comprising: treating a first intermediate compound of formula II:
##STR00224## wherein Q is a halogen, under conditions effective to
produce the product compound.
Description
[0001] This application claims benefit of U.S. Provisional Patent
Application Ser. No. 61/222,440, filed Jul. 1, 2009, and U.S.
Provisional Patent Application Ser. No. 61/329,428, filed Apr. 29,
2010, which are hereby incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to azabicycloalkane-indoles,
which are melanin-concentrating hormone (MCH-1) receptor
antagonists, pharmaceutical compositions including these compounds,
and methods of preparation and use thereof. The compounds are
useful in the treatment of obesity, anxiety, depression,
non-alcoholic fatty liver disease, and psychiatric disorders.
BACKGROUND OF THE INVENTION
[0003] Obesity and the multitude of co-morbidities associated with
obesity such as diabetes, dyslipidemia, coronary heart disease, and
certain cancers are a major concern for public health. The
currently available pharmaceutical therapies for the treatment of
obesity have limited efficacy and side effects that limit their
use. Thus, there is a significant medical need for better
pharmacotherapy for obesity.
[0004] Obesity has associated with it, economic and social costs.
Obese people, an increasing proportion of most western societies,
are regarded as having out of control feeding habits often
associated with low self-esteem. Moreover, obese persons are more
likely to have medical problems associated with or exacerbated by
the excess body weight. Examples of medical conditions caused,
exacerbated, or triggered by excessive weight include bone
fractures, pains in the knee joints, arthritis, increased risk of
hypertension, artherosclerosis, stroke, and diabetes.
[0005] Melanin-concentrating hormone (MCH) has been identified as
an orexigenic peptide that exerts an effect on food intake and body
weight regulation. MCH is a cyclic 19 amino acid neuropeptide
expressed in the zona incerta and lateral hypothalamus in response
to both energy restriction and leptin deficiency. MCH is known to
stimulate feeding when injected into the lateral ventricle of rats
and the mRNA for MCH is upregulated in the hypothalamus of
genetically obese mice (ob/ob) and in fasted control and ob/ob
animals. In addition, animals treated with MCH show increases in
glucose, insulin and leptin levels, mimicking human metabolic
syndrome (Gomori, "Chronic Infusion of MCH Causes Obesity in Mice,"
Am. J. Physiol. Endocrinol. Metab., 284:E583 (2002)). Mice lacking
MCH are hypophagic and lean with increased metabolic rate, whereas
animals over-expressing MCH gain excess weight on both standard and
high fat diets. MCH is thought to have effects on other nervous
system functions as well (Rocksz, "Biological Examination of
Melanin Concentrating Hormone 1: Multi-tasking from the
Hypothalamus," Drug News Perspect., 19(5):273 (2006)). An orphan
G-protein coupled receptor (GPCR) was recently identified as a
receptor for MCH. Disruption of the binding between MCH and the MCH
receptor, i.e. MCH antagonism, may thus be used to counteract the
effects of MCH (McBriar, "Recent Advances in the Discovery of
Melanin-Concentrating Hormone Receptor Antagonists," Curr. Opin.
Drug Disc. & Dev., 9(4):496 (2006)).
[0006] The current preferred treatment for obesity as well as Type
II non-insulin dependent diabetes is diet and exercise with a view
toward weight reduction and improved insulin sensitivity for
diabetics. Patient compliance, however, is usually poor.
[0007] The problem is compounded by the fact that there are
currently only two medications approved for the treatment of
obesity (sibutramine (MERIDIA.TM.) and orlistat (XENICAL.TM.)).
[0008] The present invention is directed to overcoming these and
other deficiencies in the art.
SUMMARY OF THE INVENTION
[0009] The present invention relates to compounds of formula I:
##STR00001##
wherein R.sup.1 is selected from the group consisting of H,
--S(O).sub.qR.sup.6, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.2 is selected from the
group consisting of H, --S(O).sub.qR.sup.6, --C(O)R.sup.6,
--C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and
heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl
is optionally substituted with from 1 to 3 substituents
independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.3 is independently selected at each
location from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, CN, C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.4 is selected from the
group consisting of H, halogen, --OR.sup.5, --NR.sup.5R.sup.6,
--NR.sup.5C(O)R.sup.6, --NR.sup.5C(O).sub.2R.sup.6,
NR.sup.6C(O)NR.sup.6R.sup.7, --S(O).sub.qR.sup.6, --CN,
--C(O)R.sup.6, --C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl is optionally substituted with from 1 to 3
substituents independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.5 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
--C(O)R.sup.7, phenyl, or benzyl, wherein phenyl or benzyl is
optionally substituted 1 to 3 times with halogen, cyano,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.6 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
phenyl, or benzyl, wherein phenyl or benzyl is optionally
substituted 1 to 3 times with halogen, cyano, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 alkoxy;
R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
phenyl; R.sup.8 and R.sup.9 are each independently H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, --C(O)R.sup.7, phenyl, or benzyl, wherein phenyl
or benzyl is optionally substituted from 1 to 3 times with a
substituent selected independently at each occurrence thereof from
the group consisting of halogen, cyano, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 alkoxy; R.sup.10 is
selected from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, CN, C(O)R.sup.6, C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9;
X is CR.sup.10, C(R.sup.10).sub.2, N, or NR.sup.10;
Y is CR.sup.10, C, or N;
Z is C, CH, or N;
[0010] L is --(CH.sub.2).sub.p--O--, --(CH.sub.2).sub.p--,
--CH.dbd.CH--, or a bond; B is aryl, heteroaryl, heterocyclyl, or
cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or
cycloalkyl is optionally substituted with from 1 to 3 substituents
selected from the group consisting of H, alkoxy, --S-alkyl,
optionally substituted C.sub.1-C.sub.6 alkyl, halogen, --CF.sub.3,
and --CN; n is 1 or 2; m is 0, 1, 2, or 3; p is from 1 to 4; q is
0, 1, or 2; and represents an optional double bond, or an oxide
thereof, a pharmaceutically acceptable salt thereof, a solvate
thereof, or prodrug thereof.
[0011] Additional aspects of the present invention include
pharmaceutical compositions comprising a compound of the invention
and a pharmaceutically acceptable carrier and, optionally, one or
more additional additive agent(s) as discussed below.
[0012] The present invention also relates to a method of treating a
disease or condition which is susceptible to treatment with a MCH-1
receptor antagonist. This method involves selecting a patient with
a disease or condition which is susceptible to treatment with a
MCH-1 antagonist and administering to the patient a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt thereof.
[0013] Another aspect of the present invention relates to a method
of treating obesity in a subject in need of weight loss. This
method involves selecting a patient in need of weight loss and
administering to the patient a therapeutically effective amount of
a compound of formula I or a pharmaceutically acceptable salt
thereof.
[0014] Yet another aspect of the present invention relates to a
method of treating obesity in a subject who has experienced weight
loss. This method involves selecting a patient who has experienced
weight loss and administering to the patient a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt thereof.
[0015] A further aspect of the present invention relates to a
method of treating anxiety. This method involves selecting a
patient with anxiety and administering to the patient a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
[0016] The present invention also relates to a method of treating
depression. This method involves selecting a patient with
depression and administering to the patient a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt thereof.
[0017] Another aspect of the present invention relates to a method
of treating non-alcoholic fatty liver disease. This method involves
selecting a patient who has non-alcoholic fatty liver disease and
administering to the patient a therapeutically effective amount of
a compound of formula I or a pharmaceutically acceptable salt
thereof.
[0018] A further aspect of the present invention relates to a
process for preparation of a compound of formula I which includes
treating a first intermediate compound of formula II:
##STR00002##
wherein Q is a halogen, under conditions effective to produce the
product compound.
[0019] It has now been found that compounds of formula I are MCH-1
receptor antagonists. This invention provides compounds that bind
to the MCH-1 receptor with high affinity. The compounds provided by
formula I are useful for the treatment of obesity, anxiety,
depression, psychiatric disorders, and other disorders described
herein. In particular, it is contemplated that the compounds of
this invention will be effective in treating obesity, including
weight loss and maintenance of weight loss in patients who have
been diagnosed with obesity by the one or more of the following
measurements: an increased body mass index, increased waist
circumference (an indicator of intra-abdominal fat), Dual Energy
X-Ray Absorptiometry (DEXA), and truncal (android) fat mass. It is
further contemplated that the compounds of the invention will be
effective in inducing improvements in certain factors measured in
these tests.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention relates to compounds of formula I:
##STR00003##
wherein R.sup.1 is selected from the group consisting of H,
--S(O).sub.qR.sup.6, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.2 is selected from the
group consisting of H, --S(O).sub.qR.sup.6, --C(O)R.sup.6,
--C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and
heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl
is optionally substituted with from 1 to 3 substituents
independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.3 is independently selected at each
location from the group consisting of H, halogen, OR.sup.S,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, --CN, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9; R.sup.4 is selected from the
group consisting of H, halogen, --OR.sup.5, --NR.sup.5R.sup.6,
--NR.sup.5C(O)R.sup.6, --NR.sup.5C(O).sub.2R.sup.6,
--NR.sup.6C(O)NR.sup.6R.sup.7, --S(O).sub.qR.sup.6, --CN,
--C(O)R.sup.6, --C(O)NR.sup.5R.sup.6, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl, wherein each of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, heterocyclyl, aryl,
and heteroaryl is optionally substituted with from 1 to 3
substituents independently selected at each occurrence thereof from
C.sub.1-C.sub.3 alkyl, halogen, --CN, --OR.sup.8,
--NR.sup.8R.sup.9, and phenyl which is optionally substituted 1-3
times with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN, --OR.sup.8, or
--NR.sup.8R.sup.9; R.sup.5 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
--C(O)R.sup.7, phenyl, or benzyl, wherein phenyl or benzyl is
optionally substituted 1 to 3 times with halogen, cyano,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.6 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
phenyl, or benzyl, wherein phenyl or benzyl is optionally
substituted 1 to 3 times with halogen, cyano, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 alkoxy;
R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or
phenyl; R.sup.8 and R.sup.9 are each independently H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, --C(O)R.sup.7, phenyl, or benzyl, wherein phenyl
or benzyl is optionally substituted from 1 to 3 times with a
substituent selected independently at each occurrence thereof from
the group consisting of halogen, cyano, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 alkoxy; R.sup.10 is
selected from the group consisting of H, halogen, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)R.sup.6,
--NR.sup.5C(O).sub.2R.sup.6, --NR.sup.6C(O)NR.sup.6R.sup.7,
--S(O).sub.qR.sup.6, --CN, --C(O)R.sup.6, --C(O)NR.sup.5R.sup.6,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each
of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally
substituted with from 1 to 3 substituents independently selected at
each occurrence thereof from C.sub.1-C.sub.3 alkyl, halogen, --CN,
--OR.sup.8, --NR.sup.8R.sup.9, and phenyl which is optionally
substituted 1-3 times with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, --CN,
--OR.sup.8, or --NR.sup.8R.sup.9;
X is CR.sup.10, C(R.sup.10).sub.2, N, or NR.sup.10;
Y is CR.sup.10, C, or N;
Z is C, CH, or N;
[0021] L is --(CH.sub.2).sub.p--O--, --(CH.sub.2).sub.p--,
--CH.dbd.CH--, or a bond; B is aryl, heteroaryl, heterocyclyl, or
cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or
cycloalkyl is optionally substituted with from 1 to 3 substituents
selected from the group consisting of H, alkoxy, --S-alkyl,
optionally substituted C.sub.1-C.sub.6 alkyl, halogen, --CF.sub.3,
and --CN; n is 1 or 2; m is 0, 1, 2, or 3; p is from 1 to 4; q is
0, 1, or 2; and represents an optional double bond, or an oxide
thereof, a pharmaceutically acceptable salt thereof, a solvate
thereof, or prodrug thereof.
[0022] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings If not defined
otherwise herein, all technical and scientific terms used herein
have the same meaning as is commonly understood by one of ordinary
skill in the art to which this invention belongs. In the event that
there is a plurality of definitions for a term herein, those in
this section prevail unless stated otherwise.
[0023] The term "alkyl" means an aliphatic hydrocarbon group which
may be straight or branched. When not otherwise restricted, the
term refers to an alkyl of 20 or fewer carbons. Lower alkyl refers
to alkyl groups having about 1 to about 6 carbon atoms in the
chain. Branched means that one or more lower alkyl groups such as
methyl, ethyl or propyl are attached to a linear alkyl chain.
Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl,
n-butyl, t-butyl, n-pentyl, 3-pentyl, and the like.
[0024] The term "alkenyl" means an aliphatic hydrocarbon group
containing a carbon-carbon double bond and which may be straight or
branched having about 2 to about 6 carbon atoms in the chain.
Preferred alkenyl groups have 2 to about 4 carbon atoms in the
chain. Branched means that one or more lower alkyl groups such as
methyl, ethyl, or propyl are attached to a linear alkenyl chain.
Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and
i-butenyl. In the present invention, the term "alkenyl" may also
refer to a hydrocarbon chain having 2 to 6 carbons containing at
least one double bond and at least one triple bond.
[0025] The term "alkynyl" means an aliphatic hydrocarbon group
containing a carbon-carbon triple bond and which may be straight or
branched having about 2 to about 6 carbon atoms in the chain.
Preferred alkynyl groups have 2 to about 4 carbon atoms in the
chain. Branched means that one or more lower alkyl groups such as
methyl, ethyl, or propyl are attached to a linear alkynyl chain.
Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl,
2-butyryl, 3-methylbutynyl, and n-pentynyl.
[0026] The term "aryl" means an aromatic monocyclic or multi-cyclic
(polycyclic) ring system of 6 to about 19 carbon atoms, preferably
of 6 to about 10 carbon atoms, and includes arylalkyl groups. The
ring system of the aryl group may be optionally substituted.
Representative aryl groups of the present invention include, but
are not limited to, groups such as phenyl, naphthyl, azulenyl,
phenanthrenyl, anthracenyl, fluorenyl, pyrenyl, triphenylenyl,
chrysenyl, and naphthacenyl.
[0027] The term "arylalkyl" means an alkyl residue attached to an
aryl ring. Examples are benzyl, phenethyl, and the like.
[0028] The term "alkoxy" means groups of from 1 to 8 carbon atoms
of a straight, branched, or cyclic configuration and combinations
thereof attached to the parent structure through an oxygen.
Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers to
groups containing one to four carbons. For the purposes of the
present patent application, alkoxy also includes methylenedioxy and
ethylenedioxy in which each oxygen atom is bonded to the atom,
chain, or ring from which the methylenedioxy or ethylenedioxy group
is pendant so as to form a ring. Thus, for example, phenyl
substituted by alkoxy may be, for example,
##STR00004##
[0029] The term "compounds of the invention", and equivalent
expressions, are meant to embrace compounds of general formula I as
hereinbefore described, which expression includes the prodrugs, the
pharmaceutically acceptable salts, the oxides, the solvates, e.g.
hydrates, and inclusion complexes of that compound, where the
context so permits, as well as any stereoisomeric form, or a
mixture of any such forms of that compound in any ratio. Inclusion
complexes are described in Remington, The Science and Practice of
Pharmacy, 19th Ed. 1:176-177 (1995), which is hereby incorporated
by reference in its entirety. The most commonly employed inclusion
complexes are those with cyclodextrins, and all cyclodextrin
complexes, natural and synthetic, are specifically encompassed
within the claims. Thus, in accordance with some embodiments of the
invention, a compound as described herein, including in the
contexts of pharmaceutical compositions, methods of treatment, and
compounds per se, is provided as the salt form. Similarly,
reference to intermediates, whether or not they themselves are
claimed, is meant to embrace their salts and solvates, where the
context so permits. For the sake of clarity, particular instances
when the context so permits are sometimes indicated in the text,
but these instances are purely illustrative and it is not intended
to exclude other instances when the context so permits.
[0030] The term "cycloalkyl" means a non-aromatic, saturated or
unsaturated, mono- or multi-cyclic ring system of about 3 to about
7 carbon atoms, preferably of about 5 to about 7 carbon atoms, and
which may include at least one double bond. Exemplary cycloalkyl
groups include, without limitation, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclophenyl, anti-bicyclopropane, and
syn-tricyclopropane.
[0031] The term "cycloalkylalkyl" means an cycloalkyl-alkyl-group
in which the cycloalkyl and alkyl are as defined herein. Exemplary
cycloalkylalkyl groups include cyclopropylmethyl and
cyclopentylmethyl. The alkyl radical and the cycloalkyl radical may
be optionally substituted as defined above.
[0032] The term "haloalkyl" means both branched and straight-chain
alkyl substituted with one or more halogen, wherein the alkyl group
is as herein described.
[0033] The term "halogen" means fluorine, chlorine, bromine, or
iodine.
[0034] The term "heteroaryl" means an aromatic monocyclic or
multi-cyclic ring system of about 5 to about 19 ring atoms,
preferably about 5 to about 10 ring atoms, in which one or more of
the atoms in the ring system is/are element(s) other than carbon,
for example, nitrogen, oxygen, or sulfur. In the case of
multi-cyclic ring system, only one of the rings needs to be
aromatic for the ring system to be defined as "heteroaryl".
Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix
aza, oxa, thia, or thio before heteroaryl means that at least a
nitrogen, oxygen, or sulfur atom, respectively, is present as a
ring atom. A nitrogen, carbon, or sulfur atom in the heteroaryl
ring may be optionally oxidized; the nitrogen may optionally be
quaternized. Representative heteroaryls include pyridyl,
2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl,
benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl,
benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl,
benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl,
cinnolinyl, pthalazinyl, quinoxalinyl,
2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,
benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,
6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,
imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,
[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,
thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl,
thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl,
thieno[3,2-c]pyrimidinyl, furo[3,2-d]pyrimidinyl,
thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,
6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl,
2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl,
2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,
benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,
3,4-dihydro-2H-benzo[b][1,4]oxazinyl,
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,
[1,2,4]triazolo[4,3-a]pyrazinyl,
3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like.
[0035] As used herein, "heterocyclyl" or "heterocycle" refers to a
stable 3- to 18-membered ring (radical) which consists of carbon
atoms and from one to five heteroatoms selected from the group
consisting of nitrogen, oxygen and sulfur. For purposes of this
invention, the heterocycle may be a monocyclic, or a polycyclic
ring system, which may include fused, bridged, or spiro ring
systems; and the nitrogen, carbon, or sulfur atoms in the
heterocycle may be optionally oxidized; the nitrogen atom may be
optionally quaternized; and the ring may be partially or fully
saturated. Examples of such heterocycles include, without
limitation, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl,
1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl,
decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl,
isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,
tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and
thiamorpholinyl sulfone. Further heterocycles and heteroaryls are
described in Katritzky et al., eds., Comprehensive Heterocyclic
Chemistry: The Structure, Reactions, Synthesis and Use of
Heterocyclic Compounds, Vol. 1-8, Pergamon Press, N.Y. (1984),
which is hereby incorporated by reference in its entirety.
[0036] The term "method of treating" means amelioration or relief
from the symptoms and/or effects associated with the disorders
described herein. As used herein, reference to "treatment" of a
patient is intended to include prophylaxis.
[0037] The term "monocyclic" used herein indicates a molecular
structure having one ring.
[0038] The term "optionally substituted" is used to indicate that a
group may have a substituent at each substitutable atom of the
group (including more than one substituent on a single atom),
provided that the designated atom's normal valency is not exceeded
and the identity of each substituent is independent of the others.
In accordance with the present invention, up to three H atoms in
each residue are replaced with alkyl, halogen, haloalkyl, hydroxy,
loweralkoxy, carboxy, carboalkoxy (also referred to as
alkoxycarbonyl), carboxamido (also referred to as
alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino,
dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino,
amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or
heteroaryloxy. "Unsubstituted" atoms bear all of the hydrogen atoms
dictated by their valency. When a substituent is keto (i.e., =0),
then two 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.
[0039] The term "pharmaceutical composition" means a composition
comprising a compound of formula I and at least one component
comprising pharmaceutically acceptable carriers, diluents,
adjuvants, excipients, or vehicles, such as preserving agents,
fillers, disintegrating agents, wetting agents, emulsifying agents,
suspending agents, sweetening agents, flavoring agents, perfuming
agents, antibacterial agents, antifungal agents, lubricating
agents, and dispensing agents, depending on the nature of the mode
of administration and dosage forms. As used herein, the term
"pharmaceutically acceptable carrier" is used to mean any carrier,
diluent, adjuvant, excipient, or vehicle, as described herein.
Examples of suspending agents include ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances.
Prevention of the action of microorganisms can be ensured by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monosterate and gelatin.
Examples of suitable carriers, diluents, solvents, or vehicles
include water, ethanol, polyols, suitable mixtures thereof,
vegetable oils (such as olive oil), and injectable organic esters
such as ethyl oleate. Examples of excipients include lactose, milk
sugar, sodium citrate, calcium carbonate, and dicalcium phosphate.
Examples of disintegrating agents include starch, alginic acids,
and certain complex silicates. Examples of lubricants include
magnesium stearate, sodium lauryl sulphate, talc, as well as high
molecular weight polyethylene glycols.
[0040] The term "pharmaceutically acceptable" means it is, within
the scope of sound medical judgment, suitable for use in contact
with the cells of humans and lower animals without undue toxicity,
irritation, allergic response and the like, and are commensurate
with a reasonable benefit/risk ratio.
[0041] The term "pharmaceutically acceptable dosage forms" means
dosage forms of the compound of the invention, and includes, for
example, tablets, dragees, powders, elixirs, syrups, liquid
preparations, including suspensions, sprays, inhalants tablets,
lozenges, emulsions, solutions, granules, capsules, and
suppositories, as well as liquid preparations for injections,
including liposome preparations. Techniques and formulations
generally may be found in Remington's Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pa., latest edition, which is hereby
incorporated by reference in its entirety.
[0042] The term "pharmaceutically acceptable prodrugs" as used
herein means those prodrugs of the compounds useful according to
the present invention which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals with undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the
invention. The term "prodrug" means compounds that are rapidly
transformed in vivo to yield the parent compound of the above
formula, for example by hydrolysis in blood. Commonly, the
conversion of prodrug to drug occurs by enzymatic processes in the
liver or blood of the mammal. Many of the compounds of the
invention may be chemically modified without absorption into the
systemic circulation, and in those cases, activation in vivo may
come about by chemical action (as in the acid-catalyzed cleavage in
the stomach) or through the intermediacy of enzymes and microflora
in the gastrointestinal GI tract. Functional groups which may be
rapidly transformed, by metabolic cleavage, in vivo form a class of
groups reactive with the carboxyl group of the compounds of this
invention. They include, but are not limited to, such groups as
alkanoyl (such as acetyl, propionyl, butyryl, and the like),
unsubstituted and substituted aroyl (such as benzoyl and
substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl),
trialkylsilyl (such as trimethyl- and triethysilyl), monoesters
formed with dicarboxylic acids (such as succinyl), and the like.
Because of the ease with which the metabolically cleavable groups
of the compounds useful according to this invention are cleaved in
vivo, the compounds bearing such groups act as pro-drugs. The
compounds bearing the metabolically cleavable groups have the
advantage that they may exhibit improved bioavailability as a
result of enhanced solubility and/or rate of absorption conferred
upon the parent compound by virtue of the presence of the
metabolically cleavable group. A thorough discussion of prodrugs is
provided in the following: Design of Prodrugs, H. Bundgaard, ed.,
Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed.,
Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design
and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter
5; "Design and Applications of Prodrugs," p. 113-191 (1991);
Advanced Drug Delivery Reviews, H. Bundgaard, 8, p. 1-38 (1992);
Journal of Pharmaceutical Sciences, 77:285 (1988); Nakeya et al,
Chem. Pharm. Bull., 32:692 (1984); Higuchi et al., "Pro-drugs as
Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series,
and Bioreversible Carriers in Drug Design, Edward B. Roche, ed.,
American Pharmaceutical Association and Pergamon Press (1987),
which are incorporated herein by reference in their entirety.
Examples of prodrugs include, but are not limited to, acetate,
formate, and benzoate derivatives of alcohol and amine functional
groups in the compounds of the invention.
[0043] The term "pharmaceutically acceptable salt" refers to salts
prepared from pharmaceutically acceptable non-toxic acids or bases
including inorganic acids and bases and organic acids and bases.
Suitable pharmaceutically acceptable acid addition salts for the
compounds of the present invention include acetic, benzenesulfonic
(besylate), benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic, and the like. Suitable pharmaceutically
acceptable base addition salts for the compounds of the present
invention include metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc or organic salts
made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine), and procaine. Pharmaceutically acceptable
salts further include, but are not limited to, amine salts, such as
but not limited to N,N' dibenzylethylenediamine, chloroprocaine,
choline, ammonia, diethanolamine and other hydroxyalkylamines,
ethylenediamine, N-methylglucamine, procaine,
N-benzylphenethylamine,
1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole,
diethylamine and other alkylamines, piperazine, and
tris(hydroxymethyl)aminomethane; alkali metal salts, such as but
not limited to lithium, potassium, and sodium; alkali earth metal
salts, such as but not limited to barium, calcium, and magnesium;
transition metal salts, such as but not limited to zinc; and other
metal salts, such as but not limited to sodium hydrogen phosphate
and disodium phosphate; and also including, but not limited to,
salts of mineral acids, such as but not limited to hydrochlorides
and sulfates; and salts of organic acids, such as but not limited
to acetates, lactates, malates, tartrates, citrates, ascorbates,
succinates, butyrates, valerates, and fumarates. Pharmaceutically
acceptable esters include, but are not limited to, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl esters of
acidic groups, including, but not limited to, carboxylic acids,
phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids,
and boronic acids. Pharmaceutical acceptable enol ethers include,
but are not limited to, derivatives of formula C.dbd.C(OR) where R
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,
or heterocyclyl. Pharmaceutically acceptable enol esters include,
but are not limited to, derivatives of formula C.dbd.C(OC(O)R)
where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl, or heterocyclyl. Pharmaceutical acceptable solvates and
hydrates are complexes of a compound with one or more solvent or
water molecules, or 1 to about 100, or 1 to about 10, or one to
about 2, 3 or 4, solvent or water molecules.
[0044] The term "polycyclic" or "multi-cyclic" used herein
indicates a molecular structure having two or more rings,
including, but not limited to, fused, bridged, or spiro rings.
[0045] Terminology related to "protecting", "deprotecting," and
"protected" functionalities occurs throughout this application.
Such terminology is well understood by persons of skill in the art
and is used in the context of processes which involve sequential
treatment with a series of reagents. In that context, a protecting
group refers to a group which is used to mask a functionality
during a process step in which it would otherwise react, but in
which reaction is undesirable. The protecting group prevents
reaction at that step, but may be subsequently removed to expose
the original functionality. The removal or "deprotection" occurs
after the completion of the reaction or reactions in which the
functionality would interfere. Thus, when a sequence of reagents is
specified, as it is in the processes of the invention, the person
of ordinary skill can readily envision those groups that would be
suitable as "protecting groups." Suitable groups for that purpose
are discussed in standard textbooks in the field of chemistry, such
as Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York (1991), which is hereby incorporated by reference in
its entirety.
[0046] The term "solvate" refers to a compound of formula I in the
solid state, wherein molecules of a suitable solvent are
incorporated in the crystal lattice. A suitable solvent for
therapeutic administration is physiologically tolerable at the
dosage administered. Examples of suitable solvents for therapeutic
administration are ethanol and water. When water is the solvent,
the solvate is referred to as a hydrate. In general, solvates are
formed by dissolving the compound in the appropriate solvent and
isolating the solvate by cooling or using an antisolvent. The
solvate is typically dried or azeotroped under ambient
conditions.
[0047] The term "therapeutically effective amount" is meant to
describe an amount of compound of the present invention effective
producing the desired therapeutic effect. Such amounts generally
vary according to a number of factors well within the purview of
ordinarily skilled artisans given the description provided herein
to determine and account for. These include, without limitation:
the particular subject, as well as its age, weight, height, general
physical condition, and medical history, the particular compound
used, as well as the carrier in which it is formulated and the
route of administration selected for it; and, the nature and
severity of the condition being treated.
[0048] Compounds described herein may contain one or more
asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms.
[0049] Each chiral center may be defined, in terms of absolute
stereochemistry, as (R)- or (S)-.
[0050] The present invention is meant to include all such possible
isomers, as well as mixtures thereof, including racemic and
optically pure forms. Optically active (R)- and (S)-, (-)- and
(+)-, or (D)- and (L)-isomers may be prepared using chiral synthons
or chiral reagents, or resolved using conventional techniques. When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers. Likewise, all tautomeric forms are also intended
to be included.
[0051] This invention also envisions the "quaternization" of any
basic nitrogen-containing groups of the compounds disclosed herein.
The basic nitrogen can be quaternized with any agents known to
those of ordinary skill in the art including, for example, lower
alkyl halides, such as methyl, ethyl, propyl and butyl chloride,
bromides and iodides; dialkyl sulfates including dimethyl, diethyl,
dibutyl and diamyl sulfates; long chain halides such as decyl,
lauryl, myristyl and stearyl chlorides, bromides and iodides; and
aralkyl halides including benzyl and phenethyl bromides. Water or
oil-soluble or dispersible products may be obtained by such
quaternization.
[0052] In the characterization of some of the substituents, it is
recited that certain substituents may combine to form rings. Unless
stated otherwise, it is intended that such rings may exhibit
various degrees of unsaturation (from fully saturated to fully
unsaturated), may include heteroatoms and may be substituted with
lower alkyl or alkoxy.
[0053] In accordance with one embodiment of the present invention,
R.sup.1 is H.
[0054] In accordance with another embodiment of the present
invention, R.sup.1 is C.sub.1-C.sub.6 alkyl, for example,
methyl.
[0055] In accordance with one embodiment of the present invention,
R.sup.2 is H. In yet another embodiment, R.sup.2 is optionally
substituted alkyl. In a preferred embodiment,
[0056] R.sup.2 is methyl.
[0057] In accordance with one embodiment of the present invention,
R.sup.3 is H, halogen, or C.sub.1-C.sub.6 alkyl.
[0058] In accordance with one embodiment of the present invention,
R.sup.4 is H, halogen, or C.sub.1-C.sub.6 alkyl.
[0059] In accordance with one embodiment of the present invention,
X is N, CH, or CH.sub.2.
[0060] In accordance with one embodiment of the present invention,
Y is N, C, or CH.
[0061] In accordance with one embodiment of the present invention,
L is a bond. In accordance with another embodiment of the present
invention, L is --CH.sub.2--O--. In yet another embodiment, L is
--CH.sub.2--CH.sub.2--.
[0062] In accordance with one embodiment of the present invention,
B is aryl. In one preferred embodiment, B is phenyl. In accordance
with another embodiment of the present invention, B is heteroaryl.
In one preferred embodiment, B is pyridinyl, for example
pyridin-2-yl or pyridin-3-yl, pyridazinyl, for example,
pyridazin-3-yl, or pyrimidinyl, for example, pyrimidin-5-yl.
[0063] As described herein, B may be optionally substituted. In one
preferred embodiment, B is unsubstituted. In another preferred
embodiment, B is substituted with one substituent selected from
methyl, trifluoromethyl, chloro, and fluoro. In yet another
preferred embodiment, B is selected from phenyl,
5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl,
6-(trifluoromethyl)pyridazin-3-yl, 6-(trifluoromethyl)pyridin-3-yl,
2-(trifluoromethyl)pyrimidin-5-yl 6-methylpyridin-3-yl,
pyridin-2-yl, 2,4-difluorophenyl, 4-chlorophenyl,
4-chloro-2-fluorophenyl, 2,4-dichlorophenyl, and
4-(trifluoromethyl)phenyl.
[0064] Within these embodiments, the selection of a particular
preferred substituent at any one of R.sup.1-R.sup.10, X, Y, Z, L, L
and B does not affect the selection of a substituent at any of the
others of R.sup.1-R.sup.10, X, Y, Z, L, and B. That is, preferred
compounds provided herein have any of the preferred substituents at
any of the positions.
[0065] In accordance with one embodiment of the present invention,
the compound has the formula:
##STR00005##
[0066] In accordance with one embodiment of the present invention,
the compound is selected from
##STR00006## ##STR00007## ##STR00008##
[0067] In accordance with another embodiment of the present
invention, the compound is selected from
##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013##
[0068] In accordance with another embodiment of the present
invention, the compound is selected from
##STR00014## ##STR00015##
[0069] Table 1, infra, lists compounds representative of
embodiments of the present invention.
[0070] One embodiment of the present invention relates to
pharmaceutically acceptable salts, or non-salt forms, of any of the
compounds of formula I described herein.
[0071] Single enantiomers, any mixture of enantiomers, including
racemic mixtures, or diastereomers (both separated and as any
mixtures) of the compounds of the present invention are also
included within the scope of the invention.
[0072] The scope of the present invention also encompasses active
metabolites of the present compounds.
[0073] The present invention also includes compounds of formula I,
wherein one or more of the atoms, e.g., C or H, are replaced by the
corresponding radioactive isotopes of that atom (e.g., C replaced
by .sup.14C and H replaced by .sup.3H), or a stable isotope of that
atom (e.g., C replaced by .sup.13C or H replaced by .sup.2H).
Radioisotopes of hydrogen, carbon, phosphorous fluorine iodine and
chlorine include .sup.3H, .sup.14C, .sup.35S, .sup.18F, .sup.32P,
.sup.33P, .sup.125I and .sup.36Cl, respectively. Compounds that
contain those radioisotopes and/or other radioisotopes of other
atoms are within the scope of this invention. Radiolabeled
compounds described herein and prodrugs thereof can generally be
prepared by methods well known to those skilled in the art.
Conveniently, such radiolabeled compounds can be prepared by
carrying out the procedures disclosed in the Examples and Schemes
by substituting a readily available radiolabeled reagent for a
non-radiolabeled reagent. Such compounds have a variety of
potential uses, e.g., as standards and reagents in determining the
binding ability of a potential pharmaceutical. In addition, in the
case of stable isotopes, such compounds may have the potential to
favorably modify the biological properties, e.g., pharmacological
and/or pharmacokinetic properties, of compounds of formula I. The
details concerning selection of suitable sites for incorporating
radioactive isotopes into the compounds are known to those skilled
in the art.
[0074] Compounds of the present invention as described herein are
useful as MCH-1 receptor antagonists. It may be found upon
examination that compounds that are not presently excluded from the
claims are not patentable to the inventors in this application. In
that case, the exclusion of species and genera in applicants'
claims are to be considered artifacts of patent prosecution and not
reflective of the inventors' concept or description of their
invention. The invention, in a compound aspect, is all compounds of
formula I, except those that are in the public's possession.
[0075] While it may be possible for compounds of formula I to be
administered as the raw chemical, it will often be preferable to
present them as part of a pharmaceutical composition. Accordingly,
another aspect of the present invention is a pharmaceutical
composition containing a therapeutically effective amount of a
compound of formula I, or a pharmaceutically acceptable salt or
solvate thereof, and a pharmaceutically acceptable carrier. The
carrier must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not deleterious to the
recipient thereof. Furthermore, when reference is made in an
independent claim to a compound or a pharmaceutically acceptable
salt thereof, it will be understood that claims which depend from
that independent claim which refer to such a compound also include
pharmaceutically acceptable salts of the compound, even if explicit
reference is not made to the salts.
[0076] Solid carriers suitable for use in the composition of the
invention include one or more substances which may also act as
flavoring agents, lubricants, solubilizers, suspending agents,
fillers, glidants, compression aides, binders,
tablet-disintegrating agents, or encapsulating materials. In
powders, the carrier may be a finely divided solid which is in
admixture with a finely divided compound of formula I. In tablets,
the formula I compound may be mixed with a carrier having the
necessary compression properties in suitable proportions and
compacted in the shape and size desired. Said powders and tablets
may contain up to 99% by weight of the formula I compound. Solid
carriers suitable for use in the composition of the invention
include calcium phosphate, magnesium stearate, talc, sugars,
lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,
sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting
waxes, and ion exchange resins.
[0077] Any pharmaceutically acceptable liquid carrier suitable for
preparing solutions, suspensions, emulsions, syrups and elixirs may
be employed in the composition of the invention. Compounds of
formula I may be dissolved or suspended in a pharmaceutically
acceptable liquid carrier such as water, an organic solvent, or a
pharmaceutically acceptable oil or fat, or a mixture thereof. Said
liquid composition may contain other suitable pharmaceutical
additives such as solubilizers, emulsifiers, buffers,
preservatives, sweeteners, flavoring agents, suspending agents,
thickening agents, coloring agents, viscosity regulators,
stabilizers, osmo-regulators, or the like. Examples of liquid
carriers suitable for oral and parenteral administration include
water (particularly containing additives as above, e.g., cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g., glycols) or their derivatives, or oils (e.g., fractionated
coconut oil and arachis oil). For parenteral administration the
carrier may also be an oily ester such as ethyl oleate or isopropyl
myristate.
[0078] In one embodiment of the present invention, the
pharmaceutical composition further comprises one or more other
therapeutic adjuncts, e.g., other compounds effective in the
treatment of obesity, anxiety, depression, or non-alcoholic fatty
liver disease, that are known to persons of skill in the art. Such
other therapeutic adjunts are described below.
[0079] Another aspect of the present invention relates to a method
of treating a disease or condition which is susceptible to
treatment with an MCH-1 receptor antagonist. This method involves
selecting a patient with a disease or condition which is
susceptible to treatment with an MCH-1 receptor antagonist and
administering to the patient a therapeutically effective amount of
a compound of formula I or a pharmaceutically acceptable salt
thereof.
[0080] Diseases or conditions which are susceptible to treatment
with an MCH-1 receptor antagonist in accordance with the present
invention include, but are not limited to, obesity, general anxiety
disorders, social phobias, vertigo, obsessive-compulsive disorders,
panic disorders, post-traumatic stress disorders, Parkinson's
Disease Psychosis, schizophrenia, cognitive decline and defects in
schizophrenia, presenile dementias, Alzheimer's Disease,
psychological disorders, depression, substance abuse disorders,
dementia associated with neurodegenerative disease, cognition
deficits, and epilepsy (see PCT Publication No. WO 2007/010275,
which is hereby incorporated by reference in its entirety).
[0081] As described above, the compounds of the present invention
are useful as MCH-1 antagonists. As used in this invention, the
term "antagonist" refers to a compound which binds to, and
decreases the activity of, a receptor in the presence of an
agonist. In the case of a G-protein coupled receptor, activation
may be measured using any appropriate second messenger system which
is coupled to the receptor in a cell or tissue in which the
receptor is expressed. Some specific, but by no means limiting,
examples of well-known second messenger systems are adenylate
cyclase, intracellular calcium mobilization, ion channel
activation, guanylate cyclase, and inositol phospholipid
hydrolysis.
[0082] As used herein, treatment means any manner in which one or
more of the symptoms of a disease or disorder are ameliorated or
otherwise beneficially altered. Treatment also encompasses any
pharmaceutical use of the compositions herein, such as use for
treating diseases or disorders in which MCH-1 receptor activity is
implicated.
[0083] In another embodiment of the present invention, the above
method further involves administering a therapeutically effective
amount of one or more therapeutic adjuncts. Suitable therapeutic
adjuncts include, but are not limited to, anti-obesity and/or
anorectic agents, anti-anxiety agents, anti-depression agents, and
anti-non-alcoholic fatty liver disease agents.
[0084] Suitable anti-obesity and/or anorectic adjuncts include, but
are not limited to, phenylpropanolamine, ephedrine,
pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter
referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such
as sibutramine), a sympathomimetic agent, a serotonergic agent
(such as dexfenfluramine or fenfluramine), a dopamine agonist (such
as bromocriptine), a melanocyte-stimulating hormone receptor
agonist or mimetic, a melanocyte-stimulating hormone analog, a
cannabinoid receptor antagonist or inverse agonist, a melanin
concentrating hormone receptor antagonist, a serotonin 5-HT.sub.6
receptor antagonist, a serotonin 5-HT.sub.2C receptor agonist, the
OB protein (hereinafter referred to as "leptin"), a leptin analog,
a leptin receptor agonist, the amylin peptide, an amylin analog, an
amylin receptor agonist, a neuropeptide Y receptor modulator, a
galanin antagonist, or a GI lipase inhibitor or decreaser (such as
orlistat). Other anorectic agents include bombesin agonists,
dehydroepiandrosterone or analogs thereof, glucocorticoid receptor
agonists and antagonists, orexin receptor antagonists, urocortin
binding protein antagonists, agonists of the glucagon-like
peptide-1 receptor such as Exendin and ciliary neurotrophic factors
such as Axokine.
[0085] Suitable anti-anxiety adjunts include, but are not limited
to, an allosteric modulator of the GABA.sub.A receptor (such as
diazepam, lorazepam, or alprazolam), a serotonin 5-HT.sub.1A
receptor partial agonist (such as buspirone), a selective serotonin
reuptake inhibitor (SSRI, such as citalopram, escitalopram,
fluoxetine, paroxetine, or sertraline), a serotonin-norepinephrine
reuptake inhibitor (SNRI, such as duloxetine or venlafaxine), a
monoamine neurotransmitter reuptake inhibitor of the tricyclic
antidepressant (TCA) class (such as amitriptyline, desipramine, or
imipramine), a combined serotonin reuptake inhibitor and
5-HT.sub.2C antagonist (such as trazodone), and an H.sub.1 receptor
antagonist (such as hydroxyzine).
[0086] Suitable anti-depression adjuncts include, but are not
limited to, a serotonin 5-HT.sub.1A receptor partial agonist (such
as buspirone), a selective serotonin reuptake inhibitor (SSRI, such
as citalopram, escitalopram, fluoxetine, paroxetine, or
sertraline), a serotonin-norepinephrine reuptake inhibitor (SNRI,
such as duloxetine or venlafaxine), a monoamine neurotransmitter
reuptake inhibitor of the tricyclic antidepressant (TCA) class
(such as amitriptyline, desipramine, or imipramine), a combined
serotonin reuptake inhibitor and 5-HT.sub.2C antagonist (such as
trazodone), a noradrenergic and specific serotonergic
antidepressant (NaSSA, such as mianserin or mirtazapine), a
norepinephrine reuptake inhibitor (NRI, such as atomoxetine or
Mazindol), a norepinephrine-dopamine reuptake inhibitor (NDRI, such
as bupropion), and a monoamine oxidase inhibitor (MAOI, such as
isocarboxazid or moclobemide).
[0087] Suitable anti-non-alcoholic fatty liver disease adjuncts
include, but are not limited to, an AMP-activated protein kinase
(AMPK) agonist (such as metformin), a peroxisome
proliferator-activated receptor (PPAR) gamma activator (such as
rosiglitazone, pioglitazone, or troglitazone), a HMG-CoA reductase
inhibitor (such as atorvastatin or simvastatin), and a PDE4
inhibitor (such as pentoxifylline).
[0088] In one embodiment, the patient is a mammal. The term
"mammal" is used in its dictionary sense. The term "mammal"
includes, for example, mice, hamsters, rats, cows, sheep, pigs,
goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats,
rabbits, guinea pigs, and primates, including humans.
[0089] The present invention also relates to a method of treating
obesity in a subject in need of weight loss. This method involves
selecting a patient in need of weight loss and administering to the
patient a therapeutically effective amount of a compound of formula
I or a pharmaceutically acceptable salt thereof.
[0090] This method further involves administering an anti-obesity
adjunct, as described above.
[0091] Yet another aspect of the present invention relates to a
method of treating obesity in a subject who has experienced weight
loss. This method involves selecting a patient who has experienced
weight loss and administering to the patient a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt thereof.
[0092] A further aspect of the present invention relates to a
method of treating anxiety. This method involves selecting a
patient with anxiety and administering to the patient a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
[0093] This method further involves administering an anti-anxiety
adjunct, as described above.
[0094] The present invention also relates to a method of treating
depression. This method involves selecting a patient with
depression and administering to the patient a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt thereof.
[0095] This method further involves administering an
anti-depression adjunct, as described above.
[0096] Another aspect of the present invention relates to a method
of treating non-alcoholic fatty liver disease. This method involves
selecting a patient who has non-alcoholic fatty liver disease and
administering to the patient a therapeutically effective amount of
a compound of formula I or a pharmaceutically acceptable salt
thereof.
[0097] This method further involves administering an
anti-non-alcoholic fatty liver disease adjunct, as described
above.
[0098] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0099] Another aspect of the present invention relates to a process
of preparing a product compound of formula I:
##STR00016##
This process involves treating a first intermediate compound of
formula II:
##STR00017##
wherein Q is a halogen, under conditions effective to produce the
product compound. R.sup.1-R.sup.4, X, Y, Z, L, and B are as defined
above.
[0100] In one embodiment, treating comprises reacting the first
intermediate with a second intermediate having the structure:
##STR00018##
[0101] Compounds useful according to the invention may be prepared
by the application or adaptation of known methods, by which is
meant methods used heretofore or described in the literature, for
example, those described by Larock, Comprehensive Organic
Transformations, Wiley-VCH publishers, New York (1989), which is
hereby incorporated by reference in its entirety.
[0102] A compound of formula I including a group containing one or
more nitrogen ring atoms, may be converted to the corresponding
compound wherein one or more nitrogen ring atom of the group is
oxidized to an N-oxide, preferably by reacting with a peracid, for
example peracetic acid in acetic acid or m-chloroperoxybenzoic acid
in an inert solvent such as dichloromethane, at a temperature from
about room temperature to reflux, preferably at elevated
temperature.
[0103] In the reactions described hereinafter, it may be necessary
to protect reactive functional groups, for example hydroxy, amino,
imino, thio, or carboxy groups, where these are desired in the
final product, to avoid their unwanted participation in the
reactions. Conventional protecting groups may be used in accordance
with standard practice and as described above.
[0104] The novel MCH-1 antagonists of formula I of this invention
can be prepared by the methods illustrated in the general reaction
schemes as, for example, described below, or by modifications
thereof, using readily available starting materials, reagents, and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants that are known in the art but are
not mentioned here. Although the syntheses depicted herein may
result in the preparation of enantiomers having a particular
stereochemistry, included within the scope of the present invention
are compounds of formula I in any stereoisomeric form, and
preparation of compounds of formula I in stereoisomeric forms other
than those depicted herein would be obvious to one of ordinary
skill in the chemical arts based on the procedures presented
herein.
Synthetic Methods
##STR00019##
[0106] Compounds of formula 3 (wherein R.sup.1 is H or alkyl;
R.sup.2 is H or a protecting group such as tert-butoxycarbonyl or
benzyloxycarbonyl; and n is 1 or 2) can be prepared from compounds
of formula 1 (or a salt thereof, wherein R.sup.1 is H or alkyl and
Z is CH or N) and compounds of formula 2 (or a salt thereof,
wherein R.sup.2 is H or a protecting group such as
tert-butoxycarbonyl or benzyloxycarbonyl; and n is 1 or 2) under
heated acidic conditions. In the case where R.sup.1 is H, optional
alkylation or protection of compound 3 can provide compounds of
formula 3 wherein R.sup.1 is alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl. In the
case where R.sup.2 is H, reductive amination, alkylation or
protection of the secondary amine can provide compounds of formula
3 wherein R.sup.2 is alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl, or p-toluenesulfonyl.
##STR00020##
[0107] Compounds of formula 7 (wherein B is aryl, heteroaryl,
heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and R.sup.13 are
each independently selected from H, alkoxy, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; and X is CH) can be prepared by treating
compounds of formula 4 (wherein X.sup.1 is chlorine, bromine or
iodine and X is CH) with compounds of formula 5 (wherein B is aryl,
heteroaryl, heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and
R.sup.13 are each independently selected from H, alkoxy, --S-alkyl,
alkyl, halo, --CF.sub.3, and --CN; Z.sup.1 is --B(OH).sub.2,
--B(OR.sup.14).sub.2, --SnR.sup.14.sub.3 or the like; and R.sup.14
is alkyl), a catalyst such as palladium(0), and a base such as
potassium carbonate to give compounds of formula 6, wherein L is a
direct bond. Alternatively, in the case where Z.sup.1 is
--CH.sub.2--OH and B is aryl, heteroaryl, heterocyclyl, or
cycloalkyl, compounds of formula 5 can be treated with a base such
as sodium hydride and compounds of formula 4 under heated
conditions to give compounds of formula 6, wherein L is
--CH.sub.2--O--. In turn, compounds of formula 6 can be treated
with acetic anhydride under heated conditions followed by methanol
and water or methanol and sodium hydroxide under ambient to heated
conditions to provide compounds of formula 7, wherein L is
--CH.sub.2--O-- or a direct bond.
##STR00021##
[0108] Alternatively, compounds of formula 7 (wherein B is aryl,
heteroaryl, heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and
R.sup.13 are each independently selected from H, alkoxy, --S-alkyl,
alkyl, halo, --CF.sub.3, and --CN; and X is CH) can be prepared by
treating compounds of formula 8 (wherein X.sup.1 is chlorine,
bromine or iodine; X.sup.2 is --O--CH.sub.3 or chlorine; and X is
CH) with compounds of formula 5 (wherein Z.sup.1 is --B(OH).sub.2,
--B(OR.sup.14).sub.2, --SnR.sup.14.sub.3 or the like; and R.sup.14
is alkyl), a catalyst such as palladium(0), and a base such as
potassium carbonate to give compounds of formula 9, wherein L is a
direct bond. Alternatively, in the case where Z.sup.1 is
--CH.sub.2--OH, compounds of formula 5 can be treated with
compounds of formula 8, a catalyst such as copper iodide, a ligand
such as 3,4,7,8-tetramethylphenanthroline, and a base such as
cesium carbonate under heated conditions to give compounds of
formula 9, wherein L is --CH.sub.2--O--. In turn, compounds of
formula 9 can be heated under acid conditions to provide compounds
of formula 7, wherein L is --CH.sub.2--O-- or a direct bond.
##STR00022##
[0109] Alternatively, compounds of formula 7 (wherein B is aryl,
heteroaryl, heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and
R.sup.13 are each independently selected from H, alkoxy, --S-alkyl,
alkyl, halo, --CF.sub.3, and --CN; and X is N) can be prepared from
compounds of formula 10 (wherein X is N and R.sup.15 is a
protecting group such as tetrahydropyran-2-yl). The hydroxyl group
on compound 10 can be converted to an appropriate activating group
to give compounds of formula 11. In the case where Z.sup.2 is
triflate, compounds of formula 10 can be treated with
trifluoromethylsulfonic anhydride or N-phenyl
trifluoromethanesulfonamide and a base such as triethylamine,
pyridine, or lithium bis(trimethylsilyl)amide under cooled
conditions to give compounds of formula 11. Treatment of compounds
of formula 11 with compounds of formula 5 (wherein B is aryl,
heteroaryl, heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and
R.sup.13 are each independently selected from H, alkoxy, --S-alkyl,
alkyl, halo, --CF.sub.3, and --CN; Z.sup.1=B(OH).sub.2,
B(OR.sup.14).sub.2, SnR.sup.14.sub.3 or the like, and
R.sup.14=alkyl), a catalyst such as palladium(0), and a base such
as potassium carbonate under heated conditions can provide
compounds of formula 12, wherein L a direct bond. Alternatively, in
the case where Z.sup.1 is --CH.sub.2--Br, compounds of formula 5
can be treated with compounds of formula 10 and a base such as
potassium carbonate to give compounds of formula 12, wherein L is
--CH.sub.2--O--. Removal of the protecting group R.sup.15 on
compound 12 can provide compounds of formula 7, wherein L is
--CH.sub.2--O-- or a direct bond.
##STR00023##
[0110] Compounds of formula 13 (wherein B is aryl, heteroaryl,
heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and R.sup.13 are
each independently selected from H, alkoxy, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; L is --CH.sub.2--O-- or a direct bond; X is
CH or N; Z is CH or N; R.sup.1 is H, alkyl, or a protecting group
such as tert-butoxycarbonyl, benzyloxycarbonyl or
p-toluenesulfonyl; R.sup.2 is H, alkyl, or a protecting group such
as tert-butoxycarbonyl, or benzyloxycarbonyl; and n is 1 or 2) can
be prepared by treating compounds of formula 3 (wherein R.sup.1 is
alkyl or a protecting group such as tert-butoxycarbonyl,
benzyloxycarbonyl, or p-toluenesulfonyl; R.sup.2 is alkyl or a
protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl;
Z is CH or N; and n is 1 or 2) under heated conditions with a
catalyst such as copper iodide, a ligand such as
trans-1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as
potassium carbonate, cesium carbonate or potassium phosphate, and
compounds of formula 7 (wherein B is aryl, heteroaryl,
heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and R.sup.13 are
each independently selected from H, alkoxy, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; L is --CH.sub.2--O-- or a direct bond; and X
is CH or N). In the case where R.sup.2 is a protecting group, the
protecting group can be removed to give compounds of formula 13
wherein R.sup.2 is H. In the case where R.sup.2 is H, reductive
amination or alkylation can provide compounds of formula 13,
wherein R.sup.2 is an alkyl group. Additionally, in the case where
R.sup.1 is a protecting group, the protecting group can be removed
to give compounds of formula 13 wherein R.sup.1 is H.
Alternatively, following removal of the R.sup.1 protecting group,
N-alkylation can give compounds of formula 13 wherein R.sup.2 is an
alkyl group.
##STR00024##
[0111] Compounds of formula 14 (wherein X is CH or N; R.sup.1 is
alkyl or a protecting group such as tert-butoxycarbonyl,
benzyloxycarbonyl, or p-toluenesulfonyl; R.sup.2 is alkyl or a
protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl;
and n is 1 or 2) can be treated with hydrogen and a catalyst such
as palladium on carbon to provide compounds of formula 15. The
hydroxyl group on compounds of formula 15 can be converted to an
appropriate activating group to give compounds of formula 16. In
the case where Z.sup.2 is triflate, compounds of formula 15 can be
treated with trifluoromethylsulfonic anhydride or N-phenyl
trifluoromethanesulfonamide and a base such as pyridine or lithium
bis(trimethylsilyl)amide under cooled conditions to give compounds
of formula 16. Treatment of compounds of formula 16 with compounds
of formula 5 (wherein B is aryl, heteroaryl, heterocyclyl, or
cycloalkyl; R.sup.11, R.sup.12, and R.sup.13 are each independently
selected from H, alkoxy, --S-alkyl, alkyl, halo, --CF.sub.3, and
--CN; Z.sup.1=B(OH).sub.2, B(OR.sup.14).sub.2, SnR.sup.14.sub.3 or
the like; and R.sup.14=alkyl), a catalyst such as palladium(0), and
a base such as potassium carbonate under heated conditions can
provide compounds of formula 13, wherein L is a direct bond.
##STR00025##
[0112] Compounds of formula 17 (wherein B is aryl, heteroaryl,
heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and R.sup.13 are
each independently selected from H, alkoxy, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; and L is --CH.sub.2--CH.sub.2--) can be
prepared by treating piperazin-2-one 17 with compounds of formula 5
(wherein Z.sup.1 is --CH.sub.2--CH.sub.2--X.sup.1; and X.sup.1 is a
leaving group such as chlorine, bromine, iodine or the like) and a
base such as di-isopropylamine to give compounds of formula 18,
wherein L is --CH.sub.2--CH.sub.2--.
##STR00026##
[0113] Compounds of formula 19 (wherein B is aryl, heteroaryl,
heterocyclyl, or cycloalkyl; R.sup.11, R.sup.12, and R.sup.13 are
each independently selected from H, alkoxy, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; L is --CH.sub.2--CH.sub.2--; Z is CH or N;
R.sup.1 is H, alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl;
R.sup.2 is H, alkyl, or a protecting group such as
tert-butoxycarbonyl, or benzyloxycarbonyl; and n is 1 or 2) can be
prepared by treating compounds of formula 3 (wherein Z is CH or N;
R.sup.1 is H, alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl;
R.sup.2 is H, alkyl, or a protecting group such as
tert-butoxycarbonyl, or benzyloxycarbonyl; and n is 1 or 2) under
heated conditions with a catalyst such as copper iodide, a ligand
such as trans-1,2-bis(methylamino)cyclohexane or
8-hydroxyquinoline, a base such as potassium carbonate, cesium
carbonate or potassium phosphate and compounds of formula 18
(wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl;
R.sup.11, R.sup.12, and R.sup.13 are each independently selected
from H, alkoxy, --S-alkyl, alkyl, halo, --CF.sub.3, and --CN; and L
is --CH.sub.2--CH.sub.2--). In the case where R.sup.2 is a
protecting group, the protecting group can be removed to give
compounds of formula 19 wherein R.sup.2 is H. In the case where
R.sup.2 is H, reductive amination or alkylation can provide
compounds of formula 19, wherein R.sup.2 is an alkyl group.
Additionally, in the case where R.sup.1 is a protecting group, the
protecting group can be removed to give compounds of formula 19
wherein R.sup.1 is H.
[0114] The present invention provides compositions containing the
compounds described herein, including, in particular,
pharmaceutical compositions comprising therapeutically effective
amounts of the compounds and pharmaceutically acceptable
carriers.
[0115] It is a further object of the present invention to provide
kits having a plurality of active ingredients (with or without
carrier) which, together, may be effectively utilized for carrying
out the novel combination therapies of the invention.
[0116] It is another object of the invention to provide a novel
pharmaceutical composition which is effective, in and of itself,
for utilization in a beneficial combination therapy because it
includes a plurality of active ingredients which may be utilized in
accordance with the invention.
[0117] The present invention also provides kits or single packages
combining one or more active ingredients useful in treating the
disease. A kit may provide (alone or in combination with a
pharmaceutically acceptable diluent or carrier) the compounds of
formula I and an additional active ingredient (alone or in
combination with diluent or carrier), as described above.
[0118] The products according to the present invention may be
presented in forms permitting administration by the most suitable
route and the invention also relates to pharmaceutical compositions
containing at least one product according to the invention which
are suitable for use in human or veterinary medicine. These
compositions may be prepared according to the customary methods,
using one or more pharmaceutically acceptable adjuvants or
excipients. The adjuvants comprise, inter alia, diluents, sterile
aqueous media, and the various non-toxic organic solvents. The
compositions may be presented in the form of tablets, pills,
granules, powders, aqueous solutions or suspensions, injectable
solutions, elixirs or syrups, and can contain one or more agents
chosen from the group comprising sweeteners, flavorings, colorings,
or stabilizers in order to obtain pharmaceutically acceptable
preparations.
[0119] The formulations of compounds of formula I include those
suitable for oral, parenteral (including subcutaneous, intradermal,
intramuscular, intraperitoneal, intravenous, and intraarticular),
rectal, colonic, and topical (including dermal, buccal, nasal,
sublingual, and intraocular) administration. The most suitable
route may depend upon the condition and disorder of the recipient.
The formulations may conveniently be presented in unit dosage form
and may be prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into
association a compound of formula I or a pharmaceutically
acceptable salt or solvate thereof ("active ingredient") with the
carrier, which constitutes one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both and then, if
necessary, shaping the product into the desired formulation.
[0120] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets, or tablets
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary, or paste.
[0121] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, lubricating, surface
active, or dispersing agent. Molded tablets may be made by molding
in a suitable machine a mixture of the powdered compound moistened
with an inert liquid diluent. The tablets may optionally be coated
or scored and may be formulated so as to provide sustained,
delayed, or controlled release of the active ingredient
therein.
[0122] The pharmaceutical compositions may include a
"pharmaceutically acceptable inert carrier", and this expression is
intended to include one or more inert excipients, which include
starches, polyols, granulating agents, microcrystalline cellulose,
diluents, lubricants, binders, disintegrating agents, and the like.
If desired, tablet dosages of the disclosed compositions may be
coated by standard aqueous or nonaqueous techniques.
"Pharmaceutically acceptable carrier" also encompasses controlled
release means.
[0123] Pharmaceutical compositions may also optionally include
other therapeutic ingredients, anti-caking agents, preservatives,
sweetening agents, colorants, flavors, desiccants, plasticizers,
dyes, and the like. Any such optional ingredient must be compatible
with the compound of formula I to insure the stability of the
formulation. The composition may contain other additives as needed,
including for example lactose, glucose, fructose, galactose,
trehalose, sucrose, maltose, raffinose, maltitol, melezitose,
stachyose, lactitol, palatinite, starch, xylitol, mannitol,
myoinositol, and the like, and hydrates thereof, and amino acids,
for example alanine, glycine and betaine, and peptides and
proteins, for example albumen.
[0124] Examples of excipients for use as the pharmaceutically
acceptable carriers and the pharmaceutically acceptable inert
carriers and the aforementioned additional ingredients include, but
are not limited to binders, fillers, disintegrants, lubricants,
anti-microbial agents, and coating agents.
[0125] The dose range for adult humans is generally from 0.001 mg
to 10 g/day orally. Tablets or other forms of presentation provided
in discrete units may conveniently contain an amount of compound of
formula I which is effective at such dosage or as a multiple of the
same, for instance, units containing 5 mg to 500 mg, usually around
10 mg to 200 mg. The precise amount of compound administered to a
patient will be the responsibility of the attendant physician. It
will be understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet time of administration, route of
administration, rate of excretion, drug combination, and the
severity of the particular disease undergoing therapy.
[0126] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration of humans may vary from about 5 to about 95% of the
total composition.
[0127] A dosage unit (e.g. an oral dosage unit) can include from,
for example, 0.01 to 0.1 mg, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1
to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to
100 mg (e.g. 0.01 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8
mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg,
18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55
mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg,
150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of
a compound described herein.
[0128] The products according to the present invention may be
administered as frequently as necessary in order to obtain the
desired therapeutic effect. Some patients may respond rapidly to a
higher or lower dose and may find much weaker maintenance doses
adequate. For other patients, it may be necessary to have long-term
treatments at the rate of 1 to 4 doses per day, in accordance with
the physiological requirements of each particular patient.
Generally, the active product may be administered orally 1 to 4
times per day. It goes without saying that, for other patients, it
will be necessary to prescribe not more than one or two doses per
day.
[0129] For additional information about pharmaceutical compositions
and their formulation, see, for example, Remington, The Science and
Practice of Pharmacy, 20.sup.th Edition (2000), which is hereby
incorporated by reference in its entirety.
[0130] The compounds of formula 1 can be administered, e.g., by
intravenous injection, intramuscular injection, subcutaneous
injection, intraperitoneal injection, topical, sublingual,
intraarticular (in the joints), intradermal, buccal, ophthalmic
(including intraocular), intranasally (including using a cannula),
or by other routes. The compounds of formula I can be administered
orally, e.g., as a tablet or cachet containing a predetermined
amount of the active ingredient, gel, pellet, paste, syrup, bolus,
electuary, slurry, capsule, powder, granules, as a solution or a
suspension in an aqueous liquid or a non-aqueous liquid, as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via
a micellar formulation (see, e.g. PCT Publication No. WO 97/11682,
which is hereby incorporated by reference in its entirety) via a
liposomal formulation (see, e.g., European Patent EP 736299 and PCT
Publication Nos. WO 99/59550 and WO 97/13500, which are hereby
incorporated by reference in their entirety), via formulations
described in PCT Publication No. WO 03/094886, which is hereby
incorporated by reference in its entirety, or in some other form.
The compounds of formula I can also be administered transdermally
(i.e. via reservoir-type or matrix-type patches, microneedles,
thermal poration, hypodermic needles, iontophoresis,
electroporation, ultrasound or other forms of sonophoresis, jet
injection, or a combination of any of the preceding methods
(Prausnitz et al., Nature Reviews Drug Discovery 3:115 (2004),
which is hereby incorporated by reference in its entirety)). The
agents can be administered locally. The compounds can be coated on
a stent. The compounds can be administered using high-velocity
transdermal particle injection techniques using the hydrogel
particle formulation described in U.S. Patent Publication No.
20020061336, which is hereby incorporated by reference in its
entirety. Additional particle formulations are described in PCT
Publication Nos. WO 00/45792, WO 00/53160, and WO 02/19989, which
are hereby incorporated by reference in their entirety. An example
of a transdermal formulation containing plaster and the absorption
promoter dimethylisosorbide can be found in PCT Publication No. WO
89/04179, which is hereby incorporated by reference in its
entirety. PCT Publication No. WO 96/11705, which is hereby
incorporated by reference in its entirety, provides formulations
suitable for transdermal administration.
[0131] The compounds can be administered in the form a suppository
or by other vaginal or rectal means. The compounds can be
administered in a transmembrane formulation as described in PCT
Publication No. WO 90/07923, which is hereby incorporated by
reference in its entirety. The compounds can be administered
non-invasively via the dehydrated particles described in U.S. Pat.
No. 6,485,706, which is hereby incorporated by reference in its
entirety. The compound can be administered in an enteric-coated
drug formulation as described in PCT Publication No. WO 02/49621,
which is hereby incorporated by reference in its entirety. The
compounds can be administered intranasaly using the formulation
described in U.S. Pat. No. 5,179,079, which is hereby incorporated
by reference in its entirety. Formulations suitable for parenteral
injection are described in PCT Publication No. WO 00/62759, which
is hereby incorporated by reference in its entirety. The compounds
can be administered using the casein formulation described in U.S.
Patent Application Publication No. 20030206939 and PCT Publication
No. WO 00/06108, which are hereby incorporated by reference in
their entirety. The compounds can be administered using the
particulate formulations described in U.S. Patent Application
Publication No. 20020034536, which is hereby incorporated by
reference in its entirety.
[0132] The compounds, alone or in combination with other suitable
components, can be administered by pulmonary route utilizing
several techniques including but not limited to intratracheal
instillation (delivery of solution into the lungs by syringe),
intratracheal delivery of liposomes, insufflation (administration
of powder formulation by syringe or any other similar device into
the lungs), and aerosol inhalation. Aerosols (e.g., jet or
ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder
inhalers (DPIs)) can also be used in intranasal applications.
Aerosol formulations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous medium and can be placed
into pressurized acceptable propellants, such as hydrofluoroalkanes
(HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof),
dichlorodifluoromethane (or other chlorofluorocarbon propellants
such as a mixture of Propellants 11, 12, and/or 114), propane,
nitrogen, and the like. Pulmonary formulations may include
permeation enhancers such as fatty acids, and saccharides,
chelating agents, enzyme inhibitors (e.g., protease inhibitors),
adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat),
preservatives (e.g., benzalkonium chloride or chlorobutanol), and
ethanol (normally up to 5% but possibly up to 20%, by weight).
Ethanol is commonly included in aerosol compositions as it can
improve the function of the metering valve and in some cases also
improve the stability of the dispersion.
[0133] Pulmonary formulations may also include surfactants which
include but are not limited to bile salts and those described in
U.S. Pat. No. 6,524,557 and references therein, which is hereby
incorporated by reference in its entirety. The surfactants
described in U.S. Pat. No. 6,524,557, which is hereby incorporated
by reference in its entirety, e.g., a C.sub.8-C.sub.16 fatty acid
salt, a bile salt, a phospholipid, or alkyl saccharide are
advantageous in that some of them also reportedly enhance
absorption of the compound in the formulation.
[0134] Also suitable in the invention are dry powder formulations
comprising a therapeutically effective amount of active compound
blended with an appropriate carrier and adapted for use in
connection with a dry-powder inhaler. Absorption enhancers that can
be added to dry powder formulations of the present invention
include those described in U.S. Pat. No. 6,632,456, which is hereby
incorporated by reference in its entirety. PCT Publication No. WO
02/080884, which is hereby incorporated by reference in its
entirety, describes new methods for the surface modification of
powders. Aerosol formulations may include U.S. Pat. No. 5,230,884,
U.S. Pat. No. 5,292,499, PCT Publication No. WO 017/8694, PCT
Publication No. WO 01/78696, U.S. Patent Application Publication
No. 2003019437, U.S. Patent Application Publication No.
20030165436, and PCT Publication No. WO 96/40089 (which includes
vegetable oil), which are hereby incorporated by reference in their
entirety. Sustained release formulations suitable for inhalation
are described in U.S. Patent Application Publication Nos.
20010036481A1, 20030232019A1, and 20040018243A1 as well as in PCT
Publication Nos. WO 01/13891, WO 02/067902, WO 03/072080, and WO
03/079885, which are hereby incorporated by reference in their
entirety.
[0135] Pulmonary formulations containing microparticles are
described in PCT Publication No. WO 03/015750, U.S. Patent
Application Publication No. 20030008013, and PCT Publication No. WO
00/00176, which are hereby incorporated by reference in their
entirety. Pulmonary formulations containing stable glassy state
powder are described in U.S. Patent Application Publication No.
20020141945 and U.S. Pat. No. 6,309,671, which are hereby
incorporated by reference in their entirety. Other aerosol
formulations are described in EP 1338272A1, PCT Publication No. WO
90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, PCT
Publication No. WO 91/04011, and U.S. Pat. No. 6,294,153, which are
hereby incorporated by reference in their entirety, and U.S. Pat.
No. 6,290,987, which is hereby incorporated by reference in its
entirety, describes a liposomal based formulation that can be
administered via aerosol or other means.
[0136] Powder formulations for inhalation are described in U.S.
Patent Application Publication No. 20030053960 and PCT Publication
No. WO 01/60341, which are hereby incorporated by reference in
their entirety. The compounds can be administered intranasally as
described in U.S. Patent Application Publication No. 20010038824,
which is hereby incorporated by reference in its entirety.
[0137] Solutions of medicament in buffered saline and similar
vehicles are commonly employed to generate an aerosol in a
nebulizer. Simple nebulizers operate on Bernoulli's principle and
employ a stream of air or oxygen to generate the spray particles.
More complex nebulizers employ ultrasound to create the spray
particles. Both types are well known in the art and are described
in standard textbooks of pharmacy such as Sprowls' American
Pharmacy and Remington's The Science and Practice of Pharmacy,
which are hereby incorporated by reference in their entirety.
[0138] Other devices for generating aerosols employ compressed
gases, usually hydrofluorocarbons and chlorofluorocarbons, which
are mixed with the medicament and any necessary excipients in a
pressurized container, these devices are likewise described in
standard textbooks such as Sprowls and Remington, which are hereby
incorporated by reference in their entirety.
[0139] Compounds of formula I can be incorporated into a liposome
to improve half-life. Compounds of formula I can also be conjugated
to polyethylene glycol (PEG) chains. Methods for pegylation and
additional formulations containing PEG-conjugates (i.e. PEG-based
hydrogels, PEG modified liposomes) can be found in Harris et al.,
Nature Reviews Drug Discovery, 2:214-221 (2003) and the references
therein, which are hereby incorporated by reference in their
entirety. Compounds of formula I can also be administered via a
nanocochleate or cochleate delivery vehicle (BioDelivery Sciences
International, Raleigh, N.C.). Compounds of formula I can also be
delivered using nanoemulsion formulations.
EXAMPLES
[0140] The Examples set forth below are for illustrative purposes
only and are not intended to limit, in any way, the scope of the
present invention.
Example 1
Analytical Methods and Materials
[0141] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Proton nuclear magnetic
resonance (NMR) spectra were obtained on Bruker spectrometers at
300, 400 or 500 MHz. Spectra are given in ppm (6) and coupling
constants, J, are reported in Hertz. Tetramethylsilane (TMS) was
used as an internal standard. Mass spectra were collected using
either a Finnigan LCQ Duo LCMS ion trap electrospray ionization
(ESI) or a mass Varian 1200L single quadrapole mass spectrometer
(ESI). High performance liquid chromatograph (HPLC) analyses were
obtained using a Luna C18(2) column (250.times.4.6 mm, Phenomenex)
or a Gemini C18 column (250.times.4.6 mm, Phenomenex) with UV
detection at 254 nm or 223 nm using a standard solvent gradient
program (Method A, B, C, or D).
Method A:
TABLE-US-00001 [0142] Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0
10.0 20 1.0 10.0 90.0 25 1.0 10.0 90.0 A = Water with 0.025%
Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic
Acid
Method B:
TABLE-US-00002 [0143] Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0
2.0 25 1.0 10.0 90.0 30 1.0 10.0 90.0 A = Water with 0.025%
Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic
Acid
Method C:
TABLE-US-00003 [0144] Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0
2.0 20 1.0 2.0 98.0 25 1.0 2.0 98.0 A = Water with 0.025%
Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic
Acid
Method D:
TABLE-US-00004 [0145] Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0
2.0 10 1.0 5.0 95.0 15 1.0 5.0 95.0 A = Water with 0.05%
Trifluoroacetic Acid B = Acetonitrile with 0.05% Trifluoroacetic
Acid
Example 2
Preparation of
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]in-
dol-3-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e
##STR00027##
[0147] 3-Bromophenylhydrazine hydrochloride (919 mg, 4.12 mmol) and
nortropanone hydrochloride (1000 mg, 6.18 mmol) were dissolved in
ethanol (5 mL), and conc. HCl (2 mL) was added. The reaction
mixture was heated at reflux for 18 h and then concentrated. The
residue was suspended in a mixture of isopropanol (25 mL) and water
(15 ml) and K.sub.2CO.sub.3 (1.70 g, 12.3 mmol) and Boc.sub.2O
(1.79 g, 8.24 mmol) were added. After 18 h, the mixture was diluted
with CH.sub.2Cl.sub.2 and the organic phase removed, dried over
Na.sub.2SO.sub.4 and concentrated. The resulting mixture of
regioisomers was purified by flash column chromatography (silica
gel, hexanes/EtOAc, 100:0 to 50:50) to give the more polar title
compound (240 mg, 15%) as a yellow solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.92-7.64 (br s, 1H), 7.42 (s, 1H), 7.34 (d,
J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.29-5.11 (br m, 1H),
4.69-4.65 (br m, 1H), 3.52-3.27 (br m, 1H), 2.44 (d, J=15.9 Hz,
1H), 2.34-2.24 (m, 1H), 2.19-2.14 (m, 1H), 1.93 (t, J=9.8 Hz, 1H),
1.46-1.43 (m, 1H), 1.43 (s, 9H).
b) tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate
##STR00028##
[0149] Sodium hydride (60% weight dispersion in mineral oil, 38 mg,
0.95 mmol) was added to a solution of tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (240 mg, 0.636 mmol) in DMF (4 mL) at room temperature under
N.sub.2. After 1 h, methyl iodide (130 mg, 0.058 mL, 0.94 mmol) was
added, and the reaction was allowed to proceed for an additional 1
h. The mixture was quenched with H.sub.2O, upon which a solid
precipitated out of solution. The solids were filtered off to
provide the title compound (248 mg, 100%) as a brown solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.40 (s, 1H), 7.35 (d, J=8.5 Hz,
1H), 7.19 (d, J=8.5 Hz, 1H), 5.30-5.10 (br m, 1H), 4.76-4.56 (br m,
1H), 3.54 (s, 3H), 3.49-3.19 (br m, 1H), 2.46 (d, J=16.0 Hz, 1H),
2.37-2.08 (m, 2H), 1.97-1.86 (m, 1H), 1.69-1.57 (m, 1H), 1.50 (s,
9H).
c) tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,7,8,9,10-hexahydro-7-
,10-iminocyclohept[b]indole-11-carboxylate
##STR00029##
[0151] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (120 mg, 0.30 mmol) and 4-(benzyloxy)pyridin-2(1H)-one
(67 mg, 0.33 mmol), CuI (62 mg, 0.33 mmol), 8-hydroxyquinoline (10
mg, 0.06 mmol) and K.sub.2CO.sub.3 (45 mg, 0.33 mmol) in DMSO (5
mL) was degassed under reduced pressure for 45 min. The suspension
was put under Ar and stirred at 135.degree. C. overnight. The
suspension was cooled, 9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
(10 mL) was added and the resulting suspension was stirred at
25.degree. C. for 30 min. The suspension was passed through a plug
of silica gel and the filtrate was washed with brine. The resulting
solution was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 90:10) afforded the title compound (65 mg, 42%) as a green oil:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.55 (d, J=8.3 Hz, 1H),
7.46-7.33 (m, 6H), 7.30 (d, J=8.0 Hz, 1H), 7.00 (d, J=6.2 Hz, 1H),
6.09 (d, J=2.5 Hz, 1H), 6.09-6.03 (dd, J=7.5, 2.6 Hz, 1H),
5.23-5.15 (br m, 1H), 5.05 (s, 2H), 4.75-4.56 (br m, 1H), 3.57 (s,
3H), 3.51-3.23 (m, 1H), 2.49 (d, J=15.7 Hz, 1H), 2.37-2.12 (m, 2H),
1.98-1.88 (m, 1H), 1.66-1.54 (m, 1H), 1.38 (s, 9H).
d)
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]-
indol-3-yl)pyridin-2(1H)-one hydrochloride
##STR00030##
[0153] TFA (1 ml) was added to a solution of tert-butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,7,8,9,10-hexahydro-7-
,10-iminocyclohept[b]indole-11-carboxylate (65 mg, 0.12 mmol) in
CH.sub.2Cl.sub.2 (2 mL) under N.sub.2, and the resulting solution
was stirred for 1 h at 25.degree. C. Saturated NaHCO.sub.3 solution
was added, and the phases were separated. The aqueous phase was
extracted with CH.sub.2Cl.sub.2, and the combined organic extracts
were dried over Na.sub.2SO.sub.4. The resulting solution was
concentrated under reduced pressure. Flash chromatography (silica
gel, CH.sub.2Cl.sub.2/(9:1 MeOH/NH.sub.4OH), 100:0 to 80:20)
afforded 20 mg of a yellow solid. 2 N HCl in Et.sub.2O (0.024 mL,
0.048 mmol) was added to a solution of the solid in MeOH (1 mL).
Concentration under vacuum provide the title compound (21 mg, 40%)
as a pink solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.64 (d,
J=8.4 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.49-7.30 (m, 6H), 7.07-7.04
(dd, J=8.3, 1.7 Hz, 1H), 6.33-6.30 (dd, J=7.6, 2.6 Hz, 1H), 6.14
(d, J=2.6 Hz, 1H), 5.23 (d, J=4.6 Hz, 1H), 5.19 (s, 2H), 4.59-4.48
(m, 1H), 3.69 (s, 3H), 3.55-3.46 (dd, J=17.3, 4.4 Hz, 1H), 3.05 (d,
J=17.3 Hz, 1H), 2.53-2.23 (m, 3H), 2.04-1.90 (m, 1H); ESI MS m/z
412 [M+H].sup.+; HPLC (Method B) 97.3% (AUC), t.sub.R=12.9 min.
Example 3
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-
-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one
hydrochloride
a) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine
[0154] (CAS Registry Number 1173155-65-1) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00031##
[0155] 3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol),
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(176 mg, 0.749 mmol), K.sub.2CO.sub.3 (310 mg, 2.25 mmol) and
PdCl.sub.2(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL).
The reaction mixture was degassed, then back-filled with N.sub.2.
The reaction mixture was stirred at 80.degree. C. in a pre-heated
oil bath for 2 hours. After cooling, the reaction was quenched with
water and extracted with CH.sub.2Cl.sub.2. The organic layer was
washed with H.sub.2O and 5% LiCl solution, dried with
Na.sub.2SO.sub.4, filtered and concentrated. Flash chromatography
(silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title
compound (115 mg, 60%) as a white solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),
7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H),
4.03 (s, 3H).
b) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one
[0156] (CAS Registry Number 1173155-66-2 (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00032##
[0157] 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115
mg, 0.451 mmol) was stirred in concentrated hydrochloric acid (20
mL) at 120.degree. C. for 18 h and then concentrated. The residue
was adjusted to pH 8 with 6 N NaOH solution, and the solids were
filtered off, washed with water and dried under vacuum to provide
the title compound (120 mg, quant) as a white solid: .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.87 (s, 1H), 8.61 (d, J=8.9 Hz,
1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.19 (s, 1H),
7.01 (dd, J=6.8, 1.6 Hz, 1H).
c) tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)--
5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00033##
[0159] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (120 mg, 0.30 mmol) and
4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (73 mg, 0.30
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (57 mg, 34%) as a yellow oil: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.10 (d, J=8.9 Hz, 1H), 7.97 (d,
J=8.9 Hz, 1H), 7.65 (d, J=6.7 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.34
(d, J=1.7 Hz, 1H), 7.28-7.20 (m, 2H), 7.08 (d, J=7.6 Hz, 1H),
5.34-5.16 (br m, 1H), 4.76-4.57 (br m, 1H), 3.61 (s, 3H), 3.53-3.26
(br m, 1H), 2.51 (d, J=16.1 Hz, 1H), 2.40-2.11 (m, 2H), 2.00-1.90
(m, 1H), 1.68-1.51 (m, 1H), 1.38 (s, 9H).
d)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one
hydrochloride
##STR00034##
[0161] tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)--
5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(56 mg, 0.12 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (34 mg, 58%) as a yellow solid: mp
235-245.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.53
(d, J=8.9 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H), 7.90 (d, J=7.1 Hz, 1H),
7.71 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.43 (d, J=1.3 Hz,
1H), 7.35-7.32 (dd, J=7.1, 2.0 Hz, 1H), 7.19-7.15 (dd, J=8.4, 1.8
Hz, 1H), 5.26 (d, J=4.6 Hz, 1H), 4.57-4.54 (m, 1H), 3.78 (s, 3H),
3.55-3.48 (dd, J=17.0, 4.6 Hz, 1H), 3.09 (d, J=17.5 Hz, 1H),
2.53-2.24 (m, 3H), 2.06-1.95 (m, 1H); ESI MS m/z 452 [M+H].sup.+;
HPLC (Method B)>99% (AUC), t.sub.R=12.4 min
Example 4
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(5-
-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
dihydrochloride
a) 2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine
[0162] (CAS Registry Number 1108184-24-2) (WO 2009/015037 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00035##
[0163] 2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(500 mg, 1.81 mmol) were reacted according to Example 3 (step a) to
provide the title compound (337 mg, 62%) as a white solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 8.31 (d, J=5.4 Hz,
1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51
(dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
[0164] (CAS Registry Number 1108184-25-3) (WO 2009/015037 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00036##
[0165] 2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine (337 mg, 1.32
mmol) was reacted according to Example 3 (step b) to provide the
title compound (289 mg, 89%) as a white solid: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.08 (s, 1H) 9.10 (s, 1H), 8.35 (dd,
J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.53 (d, J=6.8, 1H),
7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8, 1.6 Hz, 1H).
c) tert-Butyl
5-methyl-3-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00037##
[0167] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (160 mg, 0.44 mmol) and
4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (98 mg, 0.41
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (60 mg, 26%) as a yellow oil: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 9.00 (s, 1H), 8.07-8.05 (dd,
J=8.2, 1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.62-7.52 (m, 2H), 7.34
(s, 1H), 7.26 (s, 1H), 7.20-7.01 (m, 2H), 5.35-5.21 (m, 1H),
4.72-4.62 (m, 1H), 3.60 (s, 3H), 3.51-3.30 (m, 1H), 2.51 (d, J=15.8
Hz, 1H), 2.36-2.27 (m, 1H), 2.24-2.16 (m, 1H), 1.95 (t, J=9.9 Hz,
1H), 1.65-1.54 (m, 1H), 1.38 (s, 9H).
d)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
dihydrochloride
##STR00038##
[0169] tert-Butyl
5-methyl-3-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(60 mg, 0.11 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (16 mg, 28%) as a yellow solid:
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05 (s, 1H), 8.29-8.27
(dd, J=8.4, 2.0 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.1 Hz,
1H), 7.70 (d, J=8.3 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.39 (d, J=1.4
Hz, 1H), 7.25-7.24 (dd, J=7.1, 2.0 Hz, 1H), 7.17-7.14 (dd, J=8.3,
1.8 Hz, 1H), 5.26 (d, J=5.2 Hz, 1H), 4.58-4.53 (m, 1H), 3.72 (s,
3H), 3.53-3.49 (dd, J=17.2, 4.5 Hz, 1H), 3.09 (d, J=17.2 Hz, 1H),
2.53-2.35 (m, 2H), 2.32-2.27 (dd, J=11.7, 9.7 Hz, 1H), 2.03-1.96
(m, 1H); ESI MS m/z 451 [M+H].sup.+; HPLC (Method B) 98.6% (AUC),
t.sub.R=13.1 min.
Example 5
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-
-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
dihydrochloride
a) 2'-Methoxy-6-(trifluoromethyl)-3,4'-bipyridine
[0170] (CAS Registry Number 1173155-80-0) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00039##
[0171]
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g,
11 mmol) were reacted according to the procedure of Example 3 (step
a) to provide the title compound (1.1 g, 81%) as a white solid: ESI
MS m/z 255 [M+H].
b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(11-1)-one
[0172] (CAS Registry Number 1173155-81-1) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00040##
[0173] 2'-Methoxy-6-(trifluoromethyl)-3,4'-bipyridine (1.1 g, 4.3
mmol) was reacted according to the procedure of Example 3 (step b)
to provide the title compound (522 mg, 50%) as a white solid:
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 9.10
(s, 1H), 8.40 (dd, J=8.1, 1.2 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.56
(d, J=6.7 Hz, 1H), 6.81 (s, 1H), 6.63 (dd, J=6.7, 1.3 Hz, 1H).
c) tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00041##
[0175] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (120 mg, 0.30 mmol) and
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (73 mg, 0.30
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (90 mg, 54%) as a yellow oil: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.99 (s, 1H), 8.11-8.08 (dd,
J=8.0, 1.7 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.62-7.59 (m, 2H), 7.31
(d, J=1.5 Hz, 1H), 7.07-7.05 (m, 1H), 6.93 (d, J=1.5 Hz, 1H),
6.50-6.47 (dd, J=7.0, 1.6 Hz, 1H), 5.34-5.16 (br m, 1H), 4.77-4.60
(br m, 1H), 3.60 (s, 3H), 3.52-3.28 (br m, 1H), 2.51 (d, J=15.6 Hz,
1H), 2.39-2.21 (m, 2H), 1.95 (t, J=10.1 Hz, 1H), 1.65-1.54 (m, 1H),
1.38 (s, 9H).
d)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
dihydrochloride
##STR00042##
[0177] tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(90 mg, 0.16 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (40 mg, 47%) as a yellow solid: mp
228-233.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 9.10
(s, 1H), 8.43-8.39 (dd, J=8.9, 1.9 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H),
7.84 (d, J=7.1 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.5 Hz,
1H), 7.15 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H),
6.90-6.87 (dd, J=7.1, 2.0 Hz, 1H), 5.27 (d, J=4.7 Hz, 1H),
4.59-4.53 (m, 1H), 3.72 (s, 3H), 3.53-3.48 (dd, J=17.5, 4.5 Hz,
1H), 3.08 (d, J=17.1 Hz, 1H), 2.52-2.26 (m, 3H), 2.04-2.00 (m, 1H);
ESI MS m/z 451 [M+H].sup.+; HPLC (Method B)>99% (AUC),
t.sub.R=12.7 min.
Example 6
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-
-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one dihydrochloride
a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide
[0178] (CAS Registry Number 1173155-63-9) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00043##
[0179] 5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was
dissolved in DMF (20 mL), and NaH (60% weight dispersion in mineral
oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes,
4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) was added, and the
reaction mixture was heated for 1 h at 120.degree. C. Upon cooling,
the mixture was diluted with methylene chloride and washed with 5%
lithium chloride solution (5.times.), dried and concentrated.
Purification by flash column chromatography (40 g ISCO column
eluting with methylene chloride and a methanol/ammonia mixture
(10:1); gradient 100% methylene chloride to 90% methylene chloride
over 30 min at 40 mL/min) provided the title compound (1.76 g, 50%)
as a tan solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.48 (s,
1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz,
2H), 5.20 (s, 2H).
b) 4-((5-Fluoroyridin-2-yl)methoxy)pyridin-2(1H)-one
[0180] (CAS Registry Number 924311-90-0) (WO 2007/018248 to Ando et
al., which is hereby incorporated by reference in its entirety)
##STR00044##
[0181] 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g,
7.99 mmol) was heated to 140.degree. C. in acetic anhydride (80 mL)
for 5 h. The mixture was concentrated and then heated at 80.degree.
C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15
mL). The resulting black solution was concentrated to a volume of
15 mL, and the solid was filtered off, rinsed with CH.sub.2Cl.sub.2
and dried under vacuum to provide the title compound (1.29 g, 73%)
as a yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (ddd, J=8.7, 8.7, 2.9
Hz, 1H), 7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95
(dd, J=7.4, 2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).
c) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,-
7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00045##
[0183] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (140 mg, 0.36 mmol) and
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (96 mg, 0.43
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (100 mg, 52%) as a yellow oil: ESI MS
m/z 531 [M+H].sup.+.
d)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,-
10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one
dihydrochloride
##STR00046##
[0185] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,-
7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (100
mg, 0.19 mmol) was deprotected and converted to the dihydrochloride
salt according to the procedure for Example 2 (step d) to provide
the title compound (37 mg, 39%) as a white solid: mp
180-190.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.54
(d, J=2.7 Hz, 1H), 7.79-7.63 (m, 4H), 7.46 (d, J=1.6 Hz, 1H),
7.08-7.04 (dd, J=8.4, 1.8 Hz, 1H), 6.40-6.37 (dd, J=7.6, 2.7 Hz,
1H), 6.18 (d, J=2.6 Hz, 1H), 5.29 (s, 2H), 5.24 (d, J=4.7 Hz, 1H),
4.58-4.50 (m, 1H), 3.70 (s, 3H), 3.54-3.46 (dd, J=17.2, 4.9 Hz,
1H), 3.07 (d, J=17.1 Hz, 1H), 2.51-2.23 (m, 3H), 2.02-1.99 (m, 1H);
ESI MS m/z 431 [M+H].sup.+; HPLC (Method B) 98.4% (AUC),
t.sub.R=11.8 min.
Example 7
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(2-
-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one
hydrochloride
a) 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine
[0186] (CAS Registry Number 1173155-89-9) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00047##
[0187]
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3
g, 13 mmol) were reacted according to the procedure of Example 3
(step a) to provide the title compound (1.0 g, 46%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.10 (s, 2H), 8.35
(d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz, 1H), 6.98 (d, J=1.6 Hz,
1H), 4.02 (s, 3H).
b) 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one
[0188] (CAS Registry Number 1173155-90-2) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00048##
[0189] 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (900
mg, 3.5 mmol) was reacted according to the procedure of Example 3
(step b) to provide the title compound (470 mg, 56%) as an orange
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.6 (br s, 1H),
9.41 (s, 2H), 7.61 (d, J=6.8 Hz, 1H), 6.91 (s, 1H), 6.68 (dd,
J=6.8, 1.6 Hz, 1H).
c) tert-Butyl
5-methyl-3-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl)--
5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00049##
[0191] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (135 mg, 0.345 mmol) and
4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (101 mg,
0.420 mmol) were reacted following the procedure for Example 2
(step c) to provide the title compound (69 mg, 36%) as a yellow
oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.14 (s, 2H),
7.65-7.60 (m, 2H), 7.32 (s, 1H), 7.09-7.01 (m, 1H), 7.32 (s, 1H),
6.47 (d, J=6.2 Hz, 1H), 5.35-5.18 (br m, 1H), 4.76-4.58 (br m, 1H),
3.61 (s, 3H), 3.52-3.39 (br m, 1H), 2.51 (d, J=16.3 Hz, 1H),
2.37-2.17 (m, 2H), 1.99-1.89 (m, 1H), 1.67-1.53 (m, 1H), 1.38 (s,
9H).
d)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one
hydrochloride
##STR00050##
[0193] tert-Butyl
5-methyl-3-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl)--
5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(69 mg, 0.13 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (30 mg, 49%) as a yellow solid:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 9.36 (s, 2H), 7.87 (d,
J=7.1 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H),
7.16-7.13 (dd, J=8.4, 1.8 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H),
6.93-6.93 (dd, J=7.1, 2.0 Hz, 1H), 5.26 (d, J=4.7 Hz, 1H),
4.58-4.52 (m, 1H), 3.79 (s, 3H), 3.56-3.47 (dd, J=17.3, 4.4 Hz,
1H), 3.12 (dd, J=17.3, 1.4 Hz, 1H), 2.53-2.23 (m, 3H), 2.04-1.98
(m, 1H); ESI MS m/z 452 [M+H].sup.+; HPLC (Method B)>99% (AUC),
t.sub.R=12.5 min.
Example 8
Preparation of
4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-
pyridin-2(1H)-one hydrochloride
a) tert-Butyl
3-bromo-5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-ca-
rboxylate
##STR00051##
[0195] tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (1.20 g, 3.18 mmol) and tosyl chloride (770 mg, 3.89 mmol) were
added to a biphasic system of Bu.sub.4NHSO.sub.4 (50% weight
solution in H.sub.2O, 0.26 mL) in 5:3 toluene/(6 N NaOH in
H.sub.2O) (43 mL), and the resulting biphasic system was stirred at
25.degree. C. for 1 h. The phases were separated. The organic phase
was washed with H.sub.2O, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash chromatography (silica
gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded the
title compound (1.3 g, 77%) as an orange solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.30 (br m, 1H), 7.60 (br m, 2H), 7.35 (d,
J=8.6 Hz, 1H), 7.27-7.23 (m, 1H), 7.19 (d, J=8.6 Hz, 2H), 5.09-4.97
(br m, 1H), 4.59-4.56 (m, 1H), 3.52-3.41 (m, 1H), 2.87 (d, J=17.5
Hz, 1H), 2.33-2.23 (m, 4H), 2.20-2.07 (m, 1H), 1.87 (t, J=9.6 Hz,
1H), 1.66-1.57 (m, 1H), 1.47-1.12 (br m, 9H).
b) tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-tosyl-5,6,7,8,9,10-hexahydro-7,-
10-iminocyclohept[b]indole-11-carboxylate
##STR00052##
[0197] tert-Butyl
3-bromo-5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-ca-
rboxylate (400 mg, 0.75 mmol) and 4-(benzyloxy)pyridin-2(1H)-one
(150 mg, 0.75 mmol) were reacted following the procedure for
Example 2 (step c) to provide the title compound (190 mg, 39%) as a
green foam: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.15 (br s,
1H), 7.67 (d, J=8.0 Hz, 2H), 7.50-7.34 (m, 6H), 7.31-7.16 (m, 4H),
6.09-6.08 (m, 2H), 5.14-4.97 (br m, 3H), 4.63-4.54 (m, 1H),
3.63-3.46 (m, 1H), 2.90 (d, J=17.5 Hz, 1H), 2.36-2.23 (m, 4H),
2.20-2.07 (m, 1H), 1.93-1.84 (m, 1H), 1.61-1.57 (m, 1H), 1.48-1.12
(br m, 9H).
c)
4-(Benzyloxy)-1-(5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]i-
ndol-3-yl)pyridin-2(1H)-one
##STR00053##
[0199] tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-tosyl-5,6,7,8,9,10-hexahydro-7,-
10-iminocyclohept[b]indole-11-carboxylate (190 mg, 0.29 mmol) was
deprotected according to the procedure for Example 2 (step d) to
provide the title compound (131 mg, 82%) as a solid: .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.20 (d, J=1.7 Hz, 1H), 7.74 (d,
J=8.4 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.53 (d, J=9.9 Hz, 1H), 7.46
(d, J=7.9 Hz, 2H), 7.40 (dd, J=7.4, 7.4 Hz, 2H), 7.35 (d, J=7.2 Hz,
1H), 7.30 (d, J=8.2 Hz, 2H), 7.20-7.18 (dd, J=8.2, 1.8 Hz, 1H),
6.28-6.26 (dd, J=7.2, 2.6 Hz, 1H), 6.11 (d, J=2.6 Hz, 1H), 5.17 (s,
2H), 4.45 (d, J=5.4 Hz, 1H), 3.98-3.95 (m, 1H), 3.41-3.36 (dd,
J=17.7, 4.4 Hz, 1H), 2.92 (d, J=17.7 Hz, 1H), 2.33 (s, 3H),
2.16-2.08 (m, 1H), 2.05-1.97 (m, 1H), 1.92-1.85 (m, 1H), 1.52-1.47
(m, 1H).
d)
4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-y-
l)pyridin-2(1H)-one hydrochloride
##STR00054##
[0201]
4-(Benzyloxy)-1-(5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept-
[b]indol-3-yl)pyridin-2(1H)-one (130 mg, 0.24 mmol) and NaOH (594
mg, 14.8 mmol) were added to 1:1 MeOH/CH.sub.2Cl.sub.2 (20 mL)
under N.sub.2, and the resulting suspension was stirred at reflux
for 16 h. The reaction was cooled, H.sub.2O was added, and the
resulting suspension was filtered. The obtained solid was purified
by flash chromatography (silica gel, CH.sub.2Cl.sub.2/(9:1
MeOH/NH.sub.4OH), 100:0 to 80:20) afforded the free-base that was
subsequently converted to the hydrochloride salt according to the
procedure for Example 2 (step d) to provide the title compound (41
mg, 39%) as a white solid: mp 209-214.degree. C.; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.39 (s, 1H), 9.54 (br s, 1H), 9.14 (d,
J=9.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H),
7.48-7.44 (m, 2H), 7.44-7.40 (m, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H),
7.29 (d, J=1.8 Hz, 1H), 6.95-6.93 (dd, J=8.3, 1.8 Hz, 1H),
6.09-6.07 (dd, J=7.6, 2.6 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 5.18 (br
s, 1H), 5.14 (s, 2H), 4.40 (br m, 1H), 3.44-3.40 (dd, J=17.0, 4.0
Hz, 1H), 2.90 (d, J=17.0 Hz, 1H), 2.29-2.26 (m, 2H), 2.07-2.04 (m,
1H), 1.80-1.75 (m, 1H); ESI MS m/z 398 [M+H].sup.+; HPLC (Method
B)>99% (AUC), t.sub.R=12.7 min.
Example 9
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyc-
lohept[b]indol-3-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-tosyl-5,6,7-
,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00055##
[0203] tert-Butyl
3-bromo-5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-ca-
rboxylate (362 mg, 0.680 mmol) and
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (150 mg, 0.68
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (210 mg, 46%) as a yellow foam:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.47 (s, 1H), 8.16 (br s,
1H), 7.66 (d, J=7.8 Hz, 2H), 7.52-7.34 (m, 3H), 7.34-7.17 (m, 4H),
6.14-6.11 (dd, J=7.6, 2.6, 1H), 6.06 (d, J=2.4 Hz, 1H), 5.18 (s,
2H), 5.18-5.02 (m, 1H), 4.67-4.47 (m, 1H), 3.72-3.39 (m, 1H), 2.90
(d, J=17.7 Hz, 1H), 2.35-2.27 (m, 4H), 2.27-2.08 (m, 1H), 1.94-1.82
(m, 1H), 1.61-1.51 (m, 1H), 1.46-1.19 (br s, 9H).
b) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10--
hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00056##
[0205] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-tosyl-5,6,7-
,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (210
mg, 0.31 mmol) was detosylated according to the procedure for
Example 8 (step d) to provide the title compound (260 mg, >100%)
as a yellow solid: ESI MS m/z 517 [M+H].sup.+.
c)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminoc-
yclohept[b]indol-3-yl)pyridin-2(1H)-one dihydrochloride
##STR00057##
[0207] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10--
hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (260 mg
(crude), 0.31 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (65 mg, 43%) as a pink solid: mp
205-211.degree. C. (decomp.); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.42 (s, 1H), 9.63 (d, J=6.9 Hz, 1H), 9.18 (d, J=9.7 Hz,
1H), 8.62 (d, J=2.9 Hz, 1H), 7.97-7.86 (d, J=8.4 Hz, 1H), 7.68-7.63
(dd, J=8.6, 4.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.57 (d, J=7.6 Hz,
1H), 7.30 (d, J=1.6 Hz, 1H), 6.94-6.92 (dd, J=8.4, 1.9 Hz, 1H),
6.14-6.10 (dd, J=7.6, 2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.21 (s,
2H), 5.18 (br m, 1H), 4.39 (br m, 1H), 3.46-3.39 (dd, J=17.1, 4.5
Hz, 1H), 2.87 (d, J=16.9 Hz, 1H), 2.34-2.22 (m, 2H), 2.11-2.00 (m,
1H), 1.84-1.74 (m, 1H); ESI MS m/z 417 [M+H].sup.+; HPLC (Method B)
96.9% (AUC), t.sub.R=11.4 min.
Example 10
Preparation of
1-(5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-(trifluo-
romethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5-tosyl-5,6-
,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00058##
[0209] tert-Butyl
3-bromo-5-tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-ca-
rboxylate (220 mg, 0.41 mmol) and
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (100 mg, 0.41
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (150 mg, 53%) as a colorless oil: ESI
MS m/z 691 [M+H].sup.+.
b)
1-(5-Tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(-
6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
##STR00059##
[0211] tert-Butyl
3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5-tosyl-5,6-
,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(150 mg, 0.22 mmol) was deprotected according to the procedure for
Example 2 (step d) to provide the title compound (124 mg, 96%) as a
yellow solid; ESI MS m/z 591 [M+H].sup.+.
c)
1-(5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-(trifl-
uoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
##STR00060##
[0213]
1-(5-Tosyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-
-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (120 mg, 0.21
mmol) was detosylated and converted to the hydrochloride salt
according to the procedure for Example 8 (step d) to provide the
title compound (46 mg, 46%) as an orange solid: mp 215-235.degree.
C. (decomp.); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.48 (s,
1H), 9.58-9.47 (br m, 1H), 9.20-9.15 (m, 2H), 8.51-8.47 (dd, J=8.4,
1.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.84 (d, J=7.1 Hz, 1H), 7.67
(d, J=8.4 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.07-7.04 (dd, J=8.4,
1.8 Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.80-6.77 (dd, J=7.2, 2.0 Hz,
1H), 5.21 (br m, 1H), 4.42 (br m, 1H), 3.47-3.40 (dd, J=17.3, 4.4
Hz, 1H), 2.90 (d, J=16.9 Hz, 1H), 2.30-2.23 (m, 2H), 2.07 (t, J=9.8
Hz, 1H), 1.85-1.75 (m, 1H); ESI MS m/z 437 [M+H].sup.+; HPLC
(Method B)>99% (AUC), t.sub.R=12.3 min.
Example 11
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7,1-
1-imino-5H-cyclooct[b]indol-3-yl)pyridin-2(1H)-one
dihydrochloride
a) tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole--
12-carboxylate
##STR00061##
[0215] 1-(3-Bromophenyl)-1-methylhydrazine (2.64 g, 13.1 mmol) and
(3.2 g, 13 mmol) tert-butyl
3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate were reacted
according to the procedure in Example 2 (step a) to provide the
title compound (1.38 g, 26%) as a white solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.42 (d, J=6.8 Hz, 1H), 7.29 (d, J=8.0 Hz,
1H), 7.19-7.14 (m, 1H), 5.57-5.41 (m, 1H), 4.84-4.68 (m, 1H), 3.59
(s, 3H), 3.25-3.13 (ddd, J=16.3, 7.4, 7.4 Hz, 1H), 2.53 (d, J=16.5
Hz, 1H), 1.95-1.60 (m, 2H), 1.65-0.60 (m, 2H), 1.48-1.38 (m, 1H),
1.49-1.35 (m, 10H).
b) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-6,7,-
8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
##STR00062##
[0217] tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole--
12-carboxylate (130 mg, 0.32 mmol) and
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (70 mg, 0.32
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (30 mg, 17%) as a brown oil: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.48 (d, J=2.2 Hz, 1H), 7.51-7.45
(m, 3H), 7.36-7.30 (m, 1H), 7.29-7.26 (m, 1H), 7.04-6.96 (m, 1H),
6.14-6.05 (m, 2H), 5.64-5.45 (m, 1H), 5.17 (s, 2H), 4.86-4.70 (br m
1H), 3.63 (s, 3H), 3.30-3.16 (ddd, J=16.9, 7.1, 7.1 Hz, 1H), 2.57
(d, J=16.9 Hz, 1H), 1.95-1.58 (m, 5H), 1.50-1.35 (m, 10H).
c)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7-
,11-imino-5H-cyclooct[b]indol-3-yl)pyridin-2(1H)-one
dihydrochloride
##STR00063##
[0219] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-6,7,-
8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
(30 mg, 0.055 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (25 mg, 89%) as a orange solid:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.60 (s, 1H), 7.88-7.80
(ddd, J=8.2, 2.8, 2.8 Hz, 1H), 7.80-7.70 (m, 2H), 7.60 (d, J=8.4
Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.09-7.05 (dd, J=8.4, 1.8 Hz, 1H),
6.52-6.48 (dd, J=7.6, 2.8 Hz, 1H), 6.26 (d, J=2.6 Hz, 1H), 5.35 (s,
2H), 5.09 (br m 1H), 4.18-4.15 (m, 1H), 3.76 (s, 3H), 3.54-3.42
(dd, J=18.0, 7.3 Hz, 1H), 3.13 (d, J=18.0 Hz, 1H), 2.23-1.84 (m,
4H), 1.61-1.40 (m, 2H); ESI MS m/z 445 [M+H].sup.+; HPLC (Method B)
97.4% (AUC), t.sub.R=11.9 min.
Example 12
Preparation of
4-(Benzyloxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[-
b]indol-3-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-6,7,8,9,10,11-hexahydro--
7,11-imino-5H-cyclooct[b]indole-12-carboxylate
##STR00064##
[0221] tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole--
12-carboxylate (130 mg, 0.32 mmol) and
4-(benzyloxy)pyridin-2(1H)-one (64 mg, 0.32 mmol) were reacted
following the procedure for Example 2 (step c) to provide the title
compound (60 mg, 35%) as a yellow oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.51-7.26 (m, 8H), 7.03-6.96 (m, 1H), 6.12-6.03
(m, 2H), 5.61-5.45 (m, 1H), 5.02 (s, 2H), 4.86-4.70 (br m 1H), 3.63
(s, 3H), 3.30-3.18 (ddd, J=17.0, 7.4, 7.4 Hz, 1H), 2.56 (d, J=17.0
Hz, 1H), 1.97-1.78 (m, 2H), 1.72-1.56 (m, 3H), 1.51-1.33 (m,
10H).
b)
4-(Benzyloxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooc-
t[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
##STR00065##
[0223] tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-6,7,8,9,10,11-hexahydro--
7,11-imino-5H-cyclooct[b]indole-12-carboxylate (60 mg, 0.11 mmol)
was deprotected and converted to the hydrochloride salt according
to the procedure for Example 2 (step d) to provide the title
compound (45 mg, 86%) as a white solid: .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.77 (d, J=7.5 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H),
7.53 (d, J=1.7 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.42 (dd, J=2.9,
2.9 Hz, 2H), 7.39-7.35 (m, 1H), 7.09-7.07 (dd, J=8.3, 1.8 Hz, 1H),
6.54-6.52 (dd, J=7.5, 2.8 Hz, 1H), 6.31 (d, J=2.6 Hz, 1H), 5.26 (s,
2H), 5.09 (br m 1H), 4.17-4.15 (m, 1H), 3.76 (s, 3H), 3.53-3.49
(dd, J=17.9, 7.5 Hz, 1H), 3.12 (d, J=17.9 Hz, 1H), 2.20-2.07 (m,
2H), 2.02-1.89 (m, 2H), 1.62-1.56 (m, 1H), 1.50-1.39 (m, 1H); ESI
MS m/z 426 [M+H].sup.+; HPLC (Method B)>99% (AUC), t.sub.R=13.4
min.
Example 13
Preparation of
1-(5-Methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl)--
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
hydrochloride
a) tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-6,-
7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
##STR00066##
[0225] tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cycloocta[b]indole-
-12-carboxylate (260 mg, 0.64 mmol) and
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (170 mg, 0.71
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (190 mg, 52%) as a yellow oil: ESI MS
m/z 565 [M+H].sup.+.
b)
1-(5-Methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl-
)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
hydrochloride
##STR00067##
[0227] tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-6,-
7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
(190 mg, 0.33 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (105 mg, 63%) as a yellow solid:
mp 265-274.degree. C. (decomp.); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.65 (d, J=11.4 Hz, 1H), 9.20 (d, J=2.0 Hz,
1H), 9.10 (d, J=10.5 Hz, 1H), 8.51-8.48 (dd, J=8.0, 1.8 Hz, 1H),
8.05 (d, J=8.2 Hz, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.64-7.61 (m, 2H),
7.10-7.07 (dd, J=8.4, 1.7 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H),
6.83-6.80 (dd, J=7.2, 2.0 Hz, 1H), 5.05 (br m 1H), 4.09 (br m, 1H),
3.72 (s, 3H), 3.44-3.22 (m, 1H), 3.04 (d, J=17.8 Hz, 1H), 2.21-1.96
(m, 2H), 1.88-1.64 (m, 2H), 1.53-1.38 (m, 1H), 1.35-1.17 (m, 1H);
ESI MS m/z 465 [M+H].sup.+; HPLC (Method B)>99% (AUC),
t.sub.R=12.9 min.
Example 14
Preparation of
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]in-
dol-3-yl)pyridin-2(1H)-one hydrochloride (Enantiomer A)
##STR00068##
[0229] Chiral separation of
4-(benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]in-
dol-3-yl)pyridin-2(1H)-one was performed by preparative chiral
HPLC(CHIRALPAK AD column, 5 cm ID.times.50 cm L 20.mu., flow rate
110 mL/min, using 60:40:0.1 reagent alcohol/heptane/diethylamine as
the eluent, 5 mL/injection c=0.07 mol/L, R.sub.t=19 min) to give
the free base of the title compound (224 mg). The free base was
dissolved in methanol (2 mL) and treated with 2 equivalent of 2 M
HCl in Et.sub.2O (0.5 mL), and the mixture was concentrated to
provide the title compound (235 mg) as a yellow solid: Free Base:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.53 (d, J=8.5 Hz, 1H),
7.42-7.39 (m, 4H), 7.37-7.36 (m, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.26
(m, 1H), 7.00 (dd, J=6.5, 2.0 Hz, 1H), 6.08 (d, J=3.0 Hz, 1H), 6.05
(dd, J=5.0, 2.5 Hz, 1H), 5.05 (s, 2H), 4.64 (d, J=5.0 Hz, 1H),
4.16-4.13 (m, 1H), 3.54 (s, 3H), 3.26 (dd, J=12.0, 4.5 Hz, 1H),
2.56 (d, J=16.0 Hz, 1H), 2.28-2.15 (m, 3H), 2.03-1.99 (m, 1H). HCl
salt: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.66 (d, J=8.5 Hz,
1H), 7.62 (d, J=7.5 Hz, 1H), 7.48-7.45 (m, 3H), 7.43-7.40 (m, 2H),
7.38-7.34 (m, 1H), 7.08 (dd, J=6.5, 2.0 Hz, 1H), 6.36 (dd, J=5.0,
3.0 Hz, 1H), 6.17 (d, J=2.5 Hz, 1H), 5.24 (d, J=5.5 Hz, 1H), 5.20
(s, 2H), 4.55-4.53 (m, 1H), 3.70 (s, 3H), 3.52 (dd, J=12.5, 4.5 Hz,
1H), 3.09 (dd, J=16.5, 1.0 Hz, 1H), 2.47-2.37 (m, 2H), 2.30-2.25
(m, 1H), 2.00-1.95 (m, 1H); ESI MS m/z 412 [M+H].sup.+; HPLC
(Method C) 95.9% (AUC), t.sub.R=13.1 min.
Example 15
Preparation of
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]in-
dol-3-yl)pyridin-2(1H)-one hydrochloride (Enantiomer B)
##STR00069##
[0231] Chiral separation
4-(benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]in-
dol-3-yl)pyridin-2(1H)-one was performed by preparative chiral
HPLC(CHIRALPAK AD column, 5 cm ID.times.50 cm L 20.mu., flow rate
110 mL/min, using 60:40:0.1 reagent alcohol/heptane/diethylamine as
the eluent, 5 mL/injection c=0.07 mol/L, R.sub.t=24 min) to give
the free base of title compound (202 mg). The free base was
converted to the HCl salt according to the procedure of Example 14
to provide the title compound (204 mg) as a yellow solid: Free
Base: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.53 (d, J=8.5 Hz,
1H), 7.42-7.39 (m, 4H), 7.37-7.36 (m, 1H), 7.31 (d, J=7.5 Hz, 1H),
7.26 (m, 1H), 7.00 (dd, J=6.5, 2.0 Hz, 1H), 6.08 (d, J=3.0 Hz, 1H),
6.05 (dd, J=5.0, 2.5 Hz, 1H), 5.05 (s, 2H), 4.64 (d, J=5.0 Hz, 1H),
4.16-4.13 (m, 1H), 3.54 (s, 3H), 3.26 (dd, J=12.0, 4.5 Hz, 1H),
2.56 (d, J=16.0 Hz, 1H), 2.28-2.15 (m, 3H), 2.03-1.99 (m, 1H). HCl
salt: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.66 (d, J=8.5 Hz,
1H), 7.62 (d, J=7.5 Hz, 1H), 7.48-7.45 (m, 3H), 7.43-7.40 (m, 2H),
7.38-7.34 (m, 1H), 7.08 (dd, J=6.5, 2.0 Hz, 1H), 6.36 (dd, J=5.0,
3.0 Hz, 1H), 6.17 (d, J=2.5 Hz, 1H), 5.24 (d, J=5.5 Hz, 1H), 5.20
(s, 2H), 4.55-4.53 (m, 1H), 3.70 (s, 3H), 3.52 (dd, J=12.5, 4.5 Hz,
1H), 3.09 (dd, J=16.5, 1.0 Hz, 1H), 2.47-2.37 (m, 2H), 2.30-2.25
(m, 1H), 2.00-1.95 (m, 1H); ESI MS m/z 412 [M+H].sup.+; HPLC
(Method C) 98.4% (AUC), t.sub.R=13.1 min.
Example 16
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(5-
-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer B)
a) (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate
##STR00070##
[0233] Chiral separation of tert-butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (450 mg, 1.15 mmol) was performed by preparative chiral
HPLC(CHIRALPAK OJ column, 5 cm ID.times.50 cm L 20.mu., flow rate
108 mL/min, using 5:95:0.1 reagent alcohol/heptane/diethylamine as
the eluent, 40 mL/injection c=0.01 mol/L, R.sub.t=40 min) to give
the title compound (191 mg) as an off-white solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 6.52 (s, 1H), 6.47 (d, J=8.5 Hz, 1H), 6.30
(d, J=8.0 Hz, 1H), 4.38-4.25 (m, 1H), 3.82-3.73 (m, 1H), 2.67 (s,
3H), 2.53-2.39 (m, 1H), 1.60-1.56 (m, 1H), 1.45-1.37 (m, 1H),
1.32-1.24 (m, 1H), 1.06-1.01 (m, 1H), 0.76-0.70 (m, 1H), 0.55-0.46
(m, 9H); [.alpha.].sup.2.sub.D+63.5.degree. (c 0.2, methylene
chloride).
b)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer B)
##STR00071##
[0235] (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (191 mg, 0.480 mmol) and
4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (140 mg, 0.580
mmol), CuI (45.0 mg, 0.240 mmol), 8-hydroxyquinoline (35.0 mg,
0.240 mmol) and K.sub.2CO.sub.3 (132 mg, 0.960 mmol) in DMSO (10
mL) was degassed under reduced pressure for 45 min. The suspension
was put under Ar and stirred at 135.degree. C. overnight. The
suspension was cooled, 9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
(20 mL) was added, and the resulting suspension was stirred at
25.degree. C. for 30 min. The suspension was passed through a plug
of silica gel, and the filtrate was washed with brine (3.times.).
The resulting solution was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification by preparative
thin layer chromatography (silica gel, 93:6:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave a yellow
solid (122 mg). The yellow solid was dissolved in MeOH (10 mL), and
2 M HCl in Et.sub.2O (1.1 mL) was added. The reaction was allowed
to proceed for 18 h. The mixture was concentrated, and the residue
was partitioned between methylene chloride and saturated
Na.sub.2CO.sub.3 solution. The organic phase was removed, and the
aqueous phase was extracted with methylene chloride. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. Purification by preparative thin layer
chromatography (silica gel, 90:9:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave the free
base of the title compound (64 mg) as a yellow solid. The free base
was dissolved in methanol (5 mL) and treated with 2 M HCl in
Et.sub.2O (0.14 mL, 0.28 mmol), and the mixture was concentrated to
provide the title compound (70 mg, 30%) as a yellow solid: .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 9.05 (d, J=0.5 Hz, 1H), 8.28 (dd,
J=8.5, 2.5 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.0 Hz, 1H),
7.70 (d, J=8.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.39 (d, J=1.5 Hz,
1H), 7.25 (dd, J=7.0, 2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.0 Hz, 1H),
5.26 (d, J=8.0 Hz, 1H), 4.57-4.54 (m, 1H), 3.73 (s, 3H), 3.54-3.49
(dd, J=17.5, 5 Hz, 1H), 3.12-3.07 (dd, J=17.0, 1.0 Hz, 1H),
2.48-2.32 (m, 3H), 2.04-1.97 (m, 1H); ESI MS m/z 451 [M+H].sup.+;
HPLC (Method D) 97.2% (AUC), t.sub.R=7.6 min; Chiral HPLC
(Chiralpak AD, 254 nm, 40:60:0.1 reagent
alcohol/heptane/diethylamine) 98.9% (AUC), t.sub.R=31.3 min;
[.alpha.].sup.20.sub.D-1.96.degree. (c 0.2, CD.sub.3OD).
Example 17
Preparation of
5-((5-Fluoropyridin-2-yl)methoxy)-2-(5-methyl-6,7,8,9,10,11-hexahydro-7,1-
1-imino-5H-cyclooct[b]indol-3-yl)pyridazin-3(2H)-one
hydrochloride
a)
5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-
-3(2H)-one
[0236] (CAS Registry Number 1008518-41-3) (WO 2008/022979 to
Stenkamp et al., which is hereby incorporated by reference in its
entirety)
##STR00072##
[0237] 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(2.62 g, 13.4 mmol) (this compound was prepared in accordance with
the procedure of Stenkamp et al., WO 2008022979),
2-(bromomethyl)-5-fluoropyridine (7.6 g, 40.2 mmol) and
K.sub.2CO.sub.3 (9.24 g, 67 mmol) were stirred in DMF (40 ml) and
CH.sub.2Cl.sub.2 (40 ml) for 48 h. The mixture was diluted with
CH.sub.2Cl.sub.2, washed with 5% LiCl solution (4.times.) and
concentrated. The residue was purified by column chromatography (40
g ISCO column column eluting with methylene chloride and a 10:1
methanol/ammonium hydroxide mixture; gradient 100% methylene
chloride to 95% methylene chloride) to yield the title compound
(1.1 g, 27%) as a light brown solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.47 (s, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.47-7.43
(m, 2H), 6.19 (d, J=2.9 Hz, 1H), 6.03-5.98 (dd, J=10.7, 2.0 Hz,
1H), 5.12 (s, 2H), 4.18-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6
Hz, 1H), 2.21-2.00 (m, 2H), 1.75-1.60 (m, 4H).
b) 5-((5-Fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one
[0238] (CAS Registry Number 1008518-12-4)
[0239] (WO 2008/022979 to Stenkamp et al., which is hereby
incorporated by reference in its entirety)
##STR00073##
[0240]
5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyrid-
azin-3(2H)-one (1.1 g, 3.6 mmol) was stirred in MeOH (5 mL) and 2 N
HCl in Et.sub.2O (20 mL) was added. After 16 h, the mixture was
diluted with Et.sub.2O (100 mL), and the solid was filtered off.
The solid was stirred in NaHCO.sub.3 solution (15 mL) for 15
minutes and then refiltered to provide the title compound (620 mg,
78%) as a pink solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.69 (s, 1H), 8.60 (d, J=2.8 Hz, 1H), 7.85-7.78 (td, J=8.7, 2.9
Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.67-7.63 (dd, J=8.6, 4.5 Hz, 1H),
6.31 (s, 1H), 5.25 (s, 2H).
c) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-6,-
7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
##STR00074##
[0242] tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole--
12-carboxylate (260 mg, 0.640 mmol) and
5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (141 mg, 0.640
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (127 mg, 36%) as a yellow oil: ESI MS
m/z 546 [M+H].sup.+.
d)
5-((5-Fluoropyridin-2-yl)methoxy)-2-(5-methyl-6,7,8,9,10,11-hexahydro-7-
,11-imino-5H-cyclooct[b]indol-3-yl)pyridazin-3(2H)-one
hydrochloride
##STR00075##
[0244] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-6,-
7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
(127 mg, 0.230 mmol) was reacted following the procedure for
Example 2 (step d) to provide the title compound (50 mg, 45%) as a
yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.64 (d,
J=11.0 Hz, 1H), 9.04 (d, J=11.0 Hz, 1H), 8.63 (d, J=2.9 Hz, 1H),
8.00 (d, J=2.8 Hz, 1H), 7.89-7.82 (dt, J=8.7, 2.7 Hz, 1H),
7.73-7.68 (dd, J=8.7, 4.6 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.58 (d,
J=8.5 Hz, 1H), 7.13-7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.53 (d, J=2.8
Hz, 1H), 5.29 (s, 2H), 5.03 (s, 1H), 4.16-4.05 (m, 1H), 3.70 (s,
3H), 3.41-3.33 (dd, J=18.0, 7.3 Hz, 1H), 3.03 (d, J=18.0 Hz, 1H),
2.16-2.00 (m, 2H), 1.79 (d, J=13.1 Hz, 1H), 1.70 (d, J=12.3 Hz,
1H), 1.48 (d, J=12.6 Hz, 1H), 1.33-1.24 (m, 1H); ESI MS m/z 446
[M+H].sup.+; HPLC (Method B) 97.5% (AUC), t.sub.R=11.9 min.
Example 18
Preparation of
2-(5-Methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl)--
5-((6-methylpyridin-3-yl)methoxy)pyridazin-3(2H)-one
hydrochloride
a)
5-((6-Methylpyridin-3-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-
-3(2H)-one
##STR00076##
[0246] 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(2.62 g, 13.4 mmol) and 5-(bromomethyl)-2-methylpyridine (7.47 g,
40.2 mmol) were reacted following the procedure for Example 17
(step a) to provide the title compound (1.76 g, 43%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.47 (s, 1H), 7.67
(d, J=6.2 Hz, 1H), 7.62-7.59 (dd, J=7.9, 2.3 Hz, 1H), 7.20 (d,
J=8.0 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 6.03-5.99 (dd, J=10.5, 2.0
Hz, 1H), 4.97 (s, 2H), 4.15-4.08 (m, 1H), 3.78-3.69 (td, J=11.6,
2.6 Hz, 1H), 2.59 (s, 3H), 2.16-2.00 (m, 2H), 1.74-1.54 (m,
4H).
b) 5-((6-Methylpyridin-3-yl)methoxy)pyridazin-3(2H)-one
##STR00077##
[0248]
5-((6-Methylpyridin-3-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyrid-
azin-3(2H)-one (1.76 g, 0.584 mmol) was reacted following the
procedure for Example 17 (step b) to provide the title compound
(971 mg, 76%) as a white solid: ESI MS m/z 218 [M+H].sup.+.
c) tert-Butyl
3-(4-((6-methylpyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-6,-
7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
##STR00078##
[0250] tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole--
12-carboxylate (180 mg, 0.440 mmol) and
5-((6-methylpyridin-3-yl)methoxy)pyridazin-3(2H)-one (76 mg, 0.44
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (78 mg, 32%) as a yellow oil ESI MS
m/z 542 [M+H].sup.+
d)
2-(5-Methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl-
)-5-((6-methylpyridin-3-yl)methoxy)pyridazin-3(2H)-one
hydrochloride
##STR00079##
[0252] tert-Butyl
3-(4-((6-methylpyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-6,-
7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole-12-carboxylate
(78 mg, 0.14 mmol) was reacted following the procedure for Example
2 (step d) to provide the title compound (65 mg, 97%) as a white
solid; mp 190-200.degree. C. deliquesc; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.63 (d, J=10.8 Hz, 1H), 9.06 (d, J=10.3 Hz,
1H), 8.76 (d, J=1.7 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.97 (d, J=2.9
Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.57 (d,
J=8.5 Hz, 1H), 7.12-7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.58 (d, J=2.8
Hz, 1H), 5.34 (s, 2H), 5.03 (s, 1H), 4.08-4.01 (m, 1H), 3.70 (s,
3H), 3.41-3.33 (dd, J=18.0, 7.5 Hz, 1H), 3.06 (d, J=17.8 Hz, 1H),
2.63 (s, 3H), 2.17-2.01 (m, 2H), 1.90-1.61 (m, 2H), 1.59-1.44 (m,
1H), 1.32-1.23 (m, 1H); ESI MS m/z 442 [M+H].sup.+; HPLC (Method B)
98.2% (AUC), t.sub.R=9.5 min.
Example 19
Preparation of
1-(5-Methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl)--
4-.beta.6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one
hydrochloride
a)
2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine
##STR00080##
[0254] 4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol),
(6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol),
3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g,
0.74 mmol) and Cs.sub.2CO.sub.3 (7.57 g, 23.2 mmol) were combined
in toluene (15 mL) and heated to reflux under a nitrogen atmosphere
for 16 h. Upon cooling the mixture was purified by flash column
chromatography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide
the title compound (3.19 g, 72%) as a red oil: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95
(d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz,
1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
b)
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one
##STR00081##
[0256]
2-Methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (3.19
g, 11.2 mmol) was reacted according to the procedure of Example 3
(step b) to provide the title compound (2.04 g, 67%) as a white
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.2 (br s, 1H),
8.84 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.28
(d, J=7.3 Hz, 1H), 5.95 (dd, J=7.3, 2.5 Hz, 1H), 5.82 (d, J=2.4 Hz,
1H), 5.25 (s, 2H).
c) tert-Butyl
5-methyl-3-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl-12-carb-
oxylate
##STR00082##
[0258] tert-Butyl
3-bromo-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole--
12-carboxylate (230 mg, 0.570 mmol) and
4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (154
mg, 0.570 mmol) were reacted following the procedure for Example 2
(step c) to provide the title compound (171 mg, 50%) as a yellow
oil: ESI MS m/z 595 [M+H].sup.+.
d)
1-(5-Methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl-
)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2 (1H)-one
hydrochloride
##STR00083##
[0260] tert-Butyl
5-methyl-3-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indol-3-yl-12-carb-
oxylate (171 mg, 0.228 mmol) was reacted following the procedure
for Example 2 (step d) to provide the title compound (107 mg, 88%)
as a white solid: mp 240-250.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.71 (d, J=11.3 Hz, 1H), 9.12 (d, J=11.1 Hz,
1H), 8.89 (s, 1H), 8.21-8.18 (dd, J=8.1, 1.4 Hz, 1H), 8.0 (d, J=8.1
Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.51 (d,
J=1.6 Hz, 1H), 7.00-6.96 (dd, J=8.3, 1.8 Hz, 1H), 6.17-6.13 (dd,
J=7.6, 2.8 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.38 (s, 2H), 5.02 (s,
1H), 4.12-4.00 (m, 1H), 3.70 (s, 3H), 3.41-3.33 (dd, J=17.9, 7.3
Hz, 1H), 3.03 (d, J=17.9 Hz, 1H), 2.18-2.02 (m, 2H), 1.80 (d,
J=13.3 Hz, 1H), 1.70 (d, J=12.9 Hz, 1H), 1.47-1.23 (m, 2H); ESI MS
m/z 495 [M+H].sup.+; HPLC (Method B)>99% (AUC), t.sub.R=13.1
min.
Example 20
Preparation of
(-)-4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-
-yl)pyridin-2(1H)-one hydrochloride (Enantiomer B)
a) Di-tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-5,11-dicarbox-
ylate (Enantiomer B)
##STR00084##
[0262] tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (enantiomer B) was obtained from the racemate by preparative
chiral HPLC(CHIRALPAK OJ column, 5 cm ID.times.50 cm L 20.mu., flow
rate 108 mL/min, using 90:10:0.1 iso-propyl
alcohol/heptane/diethylamine as the eluent; enantiomer B was the
second peak to elute). Enantiomer B (1.55 g, 4.11 mmol) was
dissolved in DMF (20 mL), NaH (60% disp, 180 mg, 4.52 mmol) was
added, and the mixture was stirred for 15 minutes. Di-tert-butyl
dicarbonate (980 mg, 4.52 mmol) was added, and the reaction was
stirred for 1.5 h. Ethyl acetate and water were added, and the
organic layer was removed, dried and concentrated to provide the
product (1.99 g, >100%) as a tan solid: ESI MS m/z 477
[M+H].sup.+.
b) tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10-hexahydro-7,10-imino-
cyclohept[b]indole-11-carboxylate (Enantiomer B)
##STR00085##
[0264] Di-tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-5,11-dicarbox-
ylate (enantiomer B) (1.99 g (crude), 4.11 mmol estimated) and
4-(benzyloxy)pyridin-2(1H)-one (0.74 g, 3.70 mmol) were reacted
following the procedure for Example 2 (step c) to provide the title
compound (800 mg, 40%) as a yellow solid: ESI MS m/z 498
[M+H].sup.+.
c)
(-)-4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-
-3-yl)pyridin-2(1H)-one hydrochloride (Enantiomer B)
##STR00086##
[0266] tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10-hexahydro-7,10-imino-
cyclohept[b]indole-11-carboxylate (enantiomer B) (800 mg, 1.60
mmol) was reacted following the procedure for Example 2 (step d) to
provide the title compound (302 mg, 41%) as a white solid: mp
211-217.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.37 (s, 1H), 9.26-8.83 (s, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.56 (d,
J=7.6 Hz, 1H), 7.49-7.34 (m, 5H), 7.29 (d, J=1.6 Hz, 1H), 6.95-6.92
(dd, J=8.4, 1.9 Hz, 1H), 6.13-6.05 (dd, J=7.6, 2.8 Hz, 1H), 5.90
(d, J=2.8 Hz, 1H), 5.14 (s, 3H), 4.44-4.37 (m, 1H), 3.44-3.37 (dd,
J=17.2, 4.4 Hz, 1H), 2.85 (d, J=16.8 Hz, 1H), 2.25-2.19 (m, 2H),
2.07-1.98 (m, 1H), 1.79-1.75 (m, 1H); ESI MS m/z 398 [M+H].sup.+;
HPLC (Method B)>99% (AUC), t.sub.R=12.7 min;
[.alpha.].sup.22.sub.D-11.8.degree. (c 1.00, Methanol).
Example 21
Preparation of
(+)-4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-
-yl)pyridin-2(1H)-one hydrochloride (Enantiomer A)
a) Di-tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-5,11-dicarbox-
ylate (Enantiomer A)
##STR00087##
[0268] tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (enantiomer A) was obtained from the racemate by preparative
chiral HPLC(CHIRALPAK OJ column, 5 cm ID.times.50 cm L 20.mu., flow
rate 108 mL/min, using 90:10:0.1 iso-propyl
alcohol/heptane/diethylamine as the eluent; enantiomer A was the
first peak to elute). Enantiomer A (1.26 g, 3.34 mmol) was
dissolved in DMF (20 mL), NaH (60% disp, 150 mg, 3.67 mmol) was
added and the mixture was stirred for 15 minutes. Di-tert-butyl
dicarbonate (800 mg, 3.67 mmol) was added, and the reaction stirred
for 1.5 h. Ethyl acetate and water were added, and the organic
layer was removed, dried and concentrated to provide the product
(1.64 g, >100%) as a tan solid: ESI MS m/z 477 [M+H].sup.+.
b) tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10-hexahydro-7,10-imino-
cyclohept[b]indole-11-carboxylate (Enantiomer A)
##STR00088##
[0270] Di-tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-5,11-dicarbox-
ylate (enantiomer A) (1.67 g (crude), 3.34 mmol estimated) and
4-(benzyloxy)pyridin-2(1H)-one (0.60 g, 3.0 mmol) were reacted
following the procedure for Example 2 (step c) to provide the title
compound (660 mg, 40%) as a yellow solid: ESI MS m/z 498
[M+H].sup.+.
c)
(+)-4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-
-3-yl)pyridin-2(1H)-one hydrochloride (Enantiomer A)
##STR00089##
[0272] tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10-hexahydro-7,10-imino-
cyclohept[b]indole-11-carboxylate (enantiomer A) (660 mg, 1.32
mmol) was reacted following the procedure for Example 2 (step d) to
provide the title compound (269 mg, 54%) as a white solid: mp
211-212.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.41 (s, 1H), 9.58 (s, 1H), 9.16 (s, 1H), 7.60 (d, J=8.4 Hz, 1H),
7.55 (d, J=7.6 Hz, 1H), 7.49-7.34 (m, 5H), 7.29 (d, J=1.6 Hz, 1H),
6.95-6.92 (dd, J=8.4, 1.9 Hz, 1H), 6.10-6.07 (dd, J=7.6, 2.8 Hz,
1H), 5.90 (d, J=2.6 Hz, 1H), 5.18 (s, 1H), 5.14 (s, 2H), 4.48-4.25
(m, 1H), 3.46-3.39 (dd, J=17.2, 4.4 Hz, 1H), 2.88 (d, J=16.7 Hz,
1H), 2.38-2.15 (m, 2H), 2.07-1.98 (m, 1H), 1.85-1.66 (m, 1H); ESI
MS m/z 398 [M+H].sup.+; HPLC (Method B)>99% (AUC), t.sub.R=12.7
min; [.alpha.].sup.22.sub.D+5.4.degree. (c 1.00, Methanol).
Example 22
Preparation of
1-(5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-((pyridin-2-
-yl)methoxy)pyridin-2(1H)-one hydrochloride
a) 2-Chloro-4-(pyridin-2-ylmethoxy)pyridine
##STR00090##
[0274] Pyridin-2-ylmethanol (3.00 g, 27.5 mmol),
2-chloro-4-iodopyridine (6.0 g, 25 mmol), cesium carbonate (10.6 g,
32.5 mmol), CuI (0.95 g, 5.0 mmol) and 1,10-phenanthroline (0.90 g,
5.0 mmol) were stirred in toluene (15 mL) and purged with a
nitrogen stream for 10 minutes. The mixture was heated to
105.degree. C. for 16 h, allowed cool and filtered through a silica
plug eluting with ethyl acetate. The filtrate was concentrated, and
the residue was purified by column chromatography (80 g ISCO column
column eluting with ethyl acetate/hexanes; gradient 100% hexanes to
100% ethyl acetate) to provide the title compound (4.1 g, 74%) as a
white solid: ESI MS m/z 221 [M+H].sup.+.
b) 4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one
[0275] (CAS Registry Number 1008518-20-4) (WO 2007/043835 to Kim et
al., which is hereby incorporated by reference in its entirety)
##STR00091##
[0276] 2-Chloro-4-(pyridin-2-ylmethoxy)pyridine (4.10 g, 18.5 mmol)
and ammonium acetate (7.21 g, 92.3 mmol) were heated to 110.degree.
C. in a mixture of formic acid (20 mL) and water (20 mL) for 5
days. The mixture was concentrated to remove most of the liquid and
then adjusted to pH 8 with NaHCO.sub.3 solution. The resulting
solid was filtered off to provide the title compound (3.1 g, 83%)
as a white solid: ESI MS m/z 203 [M+H].sup.+.
c) tert-Butyl
3-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-5,6,7,8,9,10-hexahydro--
7,10-iminocyclohept[b]indole-11-carboxylate
##STR00092##
[0278] tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (250 mg, 0.660 mmol) and
4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one
[0279] (134 mg, 0.660 mmol) were reacted following the procedure
for Example 2 (step c) to provide the title compound (160 mg, 48%)
as a yellow oil: ESI MS m/z 499 [M+H].sup.+.
d)
1-(5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-((pyridin-
-2-yl)methoxy)pyridin-2(1H)-one hydrochloride
##STR00093##
[0281] tert-Butyl
3-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-5,6,7,8,9,10-hexahydro--
7,10-iminocyclohept[b]indole-11-carboxylate (160 mg, 0.32 mmol) was
reacted following the procedure for Example 2 (step d) to provide
the title compound (61 mg, 44%) as a pink solid: mp 220-230.degree.
C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.40 (s, 1H), 9.48
(s, 1H), 9.13 (d, J=8.6 Hz, 1H), 8.63-8.60 (m, 1H), 7.93-7.87 (td,
J=8.4, 1.8 Hz, 1H), 7.62-7.55 (m, 3H), 7.43-7.38 (m, 1H), 7.29 (d,
J=1.6 Hz, 1H), 6.96-6.93 (dd, J=8.4, 1.9 Hz, 1H), 6.14-6.11 (dd,
J=7.6, 2.8 Hz, 1H), 5.94 (d, J=2.8 Hz, 1H), 5.21 (s, 2H), 5.18 (s,
1H), 4.41 (s, 1H), 3.40-3.38 (m, 1H), 2.88 (d, J=16.8 Hz, 1H),
2.29-2.21 (m, 2H), 2.05-2.02 (m, 1H), 1.85-1.76 (m, 1H); ESI MS m/z
399 [M+H].sup.+; HPLC (Method B) 98.8% (AUC), t.sub.R=9.8 min.
Example 23
Preparation of
1-(5-Methyl-6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-((py-
ridin-2-yl)methoxy)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
5-methyl-3-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-5,6,7,8,9,10-h-
exahydro-7,10-iminocyclohept[b]indole-11-carboxylate
##STR00094##
[0283] tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (191 mg, 0.488 mmol) and
4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one (98 mg, 0.49 mmol) was
reacted following the procedure for Example 2 (step c) to provide
the title compound (118 mg, 47%) as a yellow foam: ESI MS m/z 513
[M+H].sup.+.
d)
1-(5-Methyl-6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-((-
pyridin-2-yl)methoxy)pyridin-2(1H)-one hydrochloride
##STR00095##
[0285] tert-Butyl
5-methyl-3-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-5,6,7,8,9,10-h-
exahydro-7,10-iminocyclohept[b]indole-11-carboxylate (118 mg, 0.230
mmol) was reacted following the procedure for Example 2 (step d) to
provide the title compound (60 mg, 58%) as a yellow solid: mp
175-195.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.56 (d, J=7.3 Hz, 1H), 9.16 (d, J=10.1 Hz, 1H), 8.63-8.61 (m, 1H),
7.93-7.87 (td, J=7.7, 2.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H),
7.59-7.54 (m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.43-7.38 (m, 1H),
7.01-6.94 (dd, J=8.3, 1.8 Hz, 1H), 6.16-6.13 (dd, J=7.6, 2.8 Hz,
1H), 5.96 (d, J=2.7 Hz, 1H), 5.22-5.20 (m, 3H), 4.53-4.37 (m, 1H),
3.64 (s, 3H), 3.42-3.35 (dd, J=17.3, 4.6 Hz, 1H), 3.02 (d, J=16.8
Hz, 1H), 2.29-2.21 (m, 2H), 2.11-2.02 (m, 1H), 1.85-1.75 (m, 1H);
ESI MS m/z 413 [M+H].sup.+; HPLC (Method B)>99% (AUC),
t.sub.R=10.1 min.
Example 24
Preparation of
(-)-4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro--
7,10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer B)
a) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,-
7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(Enantiomer B)
##STR00096##
[0287] (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (570 mg, 1.45 mmol),
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (354 mg, 1.60
mmol), CuI (414 mg, 2.20 mmol), 8-hydroxyquinoline (42.0 mg, 0.290
mmol) and Cs.sub.2CO.sub.3 (519 mg, 1.60 mmol) in DMSO (15 mL) was
degassed under reduced pressure for 45 min. The suspension was put
under Ar and stirred at 135.degree. C. overnight. The suspension
was cooled, 9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (20 mL) was
added, and the resulting suspension was stirred at 25.degree. C.
for 30 min. The suspension was passed through a plug of silica gel,
and the filtrate was washed with brine (3.times.). The resulting
solution was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Purification by flash column chromatography
(silica gel, 100% solvent mixture A to 30% solvent mixture B in
solvent A; solvent mixture A=30:70 ethyl acetate/hexanes; solvent
mixture B=90:10 methanol/concentrated ammonium hydroxide) gave the
title compound (415 mg, 54%) as a yellow solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.49 (s, 1H), 7.56 (d, J=8.5 Hz, 1H),
7.51-7.44 (m, 2H), 7.33-7.30 (m, 1H), 7.25 (s, 1H), 7.00-6.99 (m,
1H), 6.08 (d, J=7.0 Hz, 1H), 6.07 (s, 1H), 5.30-5.16 (m, 1H), 5.17
(s, 2H), 4.72-4.60 (m, 1H), 3.58 (s, 3H), 3.47-3.30 (m, 1H), 2.50
(d, J=16.0 Hz, 1H), 2.40-2.22 (m, 1H), 2.21-2.14 (m, 1H), 1.96-1.91
(m, 1H), 1.70-1.50 (m, 1H), 1.50-1.30 (m, 9H).
[0288] b)
(-)-4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-h-
exahydro-7,10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one
hydrochloride (Enantiomer B)
##STR00097##
[0289] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,-
7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(enantiomer B) (415 mg, 0.780 mmol) was dissolved in MeOH (20 mL),
and 2 M HCl in Et.sub.2O (4 mL) was added. The reaction was allowed
to proceed for 18 h. The mixture was concentrated, and the residue
was partitioned between methylene chloride and saturated
Na.sub.2CO.sub.3 solution. The organic phase was removed, and the
aqueous phase was extracted with methylene chloride. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. Purification by preparative thin layer
chromatography (silica gel, 90:9:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave the free
base of the title compound (158 mg) as a yellow solid. The free
base was dissolved in MeOH (10 mL) and treated with 1.25 M HCl in
MeOH (0.32 mL). The mixture was concentrated to provide the title
compound (179 mg, 59%) as an off-white solid. Free Base: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.49 (d, J=2.5 Hz, 1H), 7.54-7.44
(m, 3H), 7.33 (d, J=7.5 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.98 (dd,
J=8.5, 2.0 Hz, 1H), 6.09-6.06 (m, 2H), 5.17 (s, 2H), 4.59-4.58 (m,
1H), 4.12-4.09 (m, 1H), 3.54 (s, 3H), 3.20-3.15 (dd, J=16.0, 4.5
Hz, 1H), 2.53 (d, J=16.0 Hz, 1H), 2.23-2.18 (m, 1H), 2.15-2.10 (m,
1H), 2.01-1.97 (m, 1H), 1.60-1.53 (m, 1H); HPLC (Method D) 98.4%
(AUC), t.sub.R=6.7 min. HCl salt: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.50 (s, 1H), 7.72-7.64 (m, 2H), 7.62 (d, J=8.5 Hz, 1H),
7.59 (d, J=7.5 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.5,
2.0 Hz, 1H), 6.32 (dd, J=7.5, 2.5 Hz, 1H), 6.12 (d, J=3.0 Hz, 1H),
5.26 (s, 2H), 5.10-5.08 (m, 1H), 4.45-4.42 (m, 1H), 3.68 (s, 3H),
3.44 (dd, J=17.0, 4.5 Hz, 1H), 2.98 (dd, J=17.0, 1.0 Hz, 1H),
2.41-2.28 (m, 2H), 2.24-2.19 (m, 1H), 1.94-1.88 (m, 1H); ESI MS m/z
431 [M+H].sup.+; HPLC (Method C)>99% (AUC), t.sub.R=6.7 min;
Chiral HPLC (Chiralpak OD, 225 nm, 35:65:0.1 reagent
alcohol/heptane/trifluoroacetic acid) 100% (AUC), t.sub.R=5.8 min;
[.alpha.].sup.20.sub.D-8.7.degree. (c 0.1, CD.sub.3OD).
Example 25
Preparation of
(+)-4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro--
7,10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer A)
a) (-)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (Enantiomer A)
##STR00098##
[0291] Chiral separation of tert-butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (450 mg, 1.15 mmol) was performed by preparative chiral
HPLC according to the procedure for Example 16 (step a) to provide
the title compound (207 mg) as an off-white solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 6.52 (s, 1H), 6.48 (d, J=8.5 Hz, 1H), 6.30
(d, J=7.5 Hz, 1H), 4.42-4.25 (m, 1H), 3.82-3.73 (m, 1H), 2.67 (s,
3H), 2.53-2.36 (m, 1H), 1.60-1.56 (m, 1H), 1.42-1.38 (m, 1H),
1.32-1.24 (m, 1H), 1.06-1.01 (m, 1H), 0.76-0.70 (m, 1H), 0.55-0.46
(m, 9H); [.alpha.].sup.20.sub.D-62.1.degree. (c 0.2, methylene
chloride).
b) tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,-
7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(Enantiomer A)
##STR00099##
[0293] (-)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer A) (600 mg, 1.53 mmol),
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (373 mg, 1.69
mmol), CuI (437 mg, 2.30 mmol), 8-hydroxyquinoline (44.4 mg, 0.300
mmol) and Cs.sub.2CO.sub.3 (548 mg, 1.69 mmol) in DMSO (15 mL) were
reacted following the procedure for Example 2 (step c) to provide
the title compound (434 mg, 53%) as a yellow solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.49 (s, 1H), 7.56 (d, J=8.5 Hz, 1H),
7.51-7.44 (m, 2H), 7.33-7.30 (m, 1H), 7.25 (s, 1H), 7.00-6.99 (m,
1H), 6.08 (d, J=7.5 Hz, 1H), 6.07 (s, 1H), 5.30-5.16 (m, 1H), 5.17
(s, 2H), 4.72-4.60 (m, 1H), 3.58 (s, 3H), 3.47-3.30 (m, 1H), 2.50
(d, J=16.0 Hz, 1H), 2.40-2.22 (m, 1H), 2.21-2.14 (m, 1H), 1.96-1.91
(m, 1H), 1.70-1.50 (m, 1H), 1.50-1.30 (m, 9H).
c)
(+)-4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-hexahydr-
o-7,10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer A)
##STR00100##
[0295] tert-Butyl
3-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-5,6,-
7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(enantiomer A) (434 mg, 0.820 mmol) was deprotected and converted
to the hydrochloride salt according to the procedure for Example 2
(step d) to provide the title compound (206 mg, 65%) as an
off-white solid. Free Base: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.48 (d, J=3.0 Hz, 1H), 7.52-7.44 (m, 3H), 7.33 (d, J=7.5
Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.98 (dd, J=8.5, 2.0 Hz, 1H),
6.09-6.06 (m, 2H), 5.16 (s, 2H), 4.64-4.62 (m, 1H), 4.17-4.15 (m,
1H), 3.47 (s, 3H), 3.22-3.17 (dd, J=16.0, 4.0 Hz, 1H), 2.53 (d,
J=16.0 Hz, 1H), 2.25-2.15 (m, 2H), 2.03-1.98 (m, 1H), 1.60-1.54 (m,
1H); HPLC (Method D) 98.0% (AUC), t.sub.R=6.6 min. HCl salt:
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.51 (d, J=2.5 Hz, 1H),
7.72-7.65 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H),
7.43 (d, J=1.5 Hz, 1H), 7.04 (dd, J=8.5, 2.0 Hz, 1H), 6.32 (dd,
J=7.5, 2.5 Hz, 1H), 6.12 (d, J=3.0 Hz, 1H), 5.26 (s, 2H), 5.20-5.19
(m, 1H), 4.53-4.50 (m, 1H), 3.69 (s, 3H), 3.48 (dd, J=17.0, 4.5 Hz,
1H), 3.05 (dd, J=17.0, 1.0 Hz, 1H), 2.46-2.33 (m, 2H), 2.28-2.23
(m, 1H), 1.99-1.93 (m, 1H); ESI MS m/z 431 [M+H].sup.+; HPLC
(Method C) 99.0% (AUC), t.sub.R=6.7 min; Chiral HPLC (Chiralpak OD,
225 nm, 35:65:0.1 reagent alcohol/heptane/trifluoroacetic acid)
100% (AUC), t.sub.R=14.1 min; [.alpha.].sup.20.sub.D+4.7.degree. (c
0.1, CD.sub.3OD).
Example 26
Preparation of
4-(Benzyloxy)-1-(5,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept-
[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
##STR00101##
[0297]
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohep-
t[b] indol-3-yl)pyridin-2(1H)-one (100 mg, 0.24 mmol) was reacted
following the procedure for Example 31 (step b) to provide the
title compound (70 mg, 69%) as a white solid: mp 121-128.degree.
C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.0 (s, 0.5H),
10.30 (s, 0.5H), 7.61-7.4 (m, 2H), 7.49-7.34 (m, 6H), 7.03-6.97
(dt, J=8.4, 1.8 Hz, 1H), 6.12-6.09 (dd, J=7.6, 2.7 Hz, 1H), 5.97
(d, J=2.7 Hz, 1H), 5.15 (s, 2H), 5.11-5.08 (m, 1H), 4.32-4.25 (m,
1H), 3.66 (s, 1.5H), 3.65 (s, 1.5H), 3.53-3.51 (m, 1H), 3.09-3.00
(m, 1H), 2.86 (d, J=5.1 Hz, 1.5H), 2.66 (d, J=5.1 Hz, 1.5H),
2.48-2.20 (m, 2H), 2.11-2.01 (m, 1H), 1.94-1.84 (m, 1H); ESI MS m/z
426 [M+H].sup.+; HPLC (Method B)>99% (AUC), t.sub.R=13.1
min.
Example 27
Preparation of
1-(11-Acetyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol--
3-yl)-4-(benzyloxy)pyridin-2(1H)-one
##STR00102##
[0299]
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohep-
t[b]indol-3-yl)pyridin-2(1H)-one (100 mg, 0.24 mmol) was stirred in
a mixture of CH.sub.2Cl.sub.2 (4 mL) and saturated sodium
bicarbonate solution (4 mL), and acetyl chloride (.about.0.2 mL)
was added. After 30 minutes, the mixture was concentrated and
purified by flash chromatography (12 g ISCO column eluting with
methylene chloride and a methanol/ammonia mixture (10:1); gradient
100% methylene chloride to 85% methylene chloride over 30 min) to
provide the title compound (92 mg, 84%) as a white solid and as a
mixture of rotamers: mp 91-96.degree. C. deliquesc; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 7.64-7.55 (m, 2H), 7.49-7.34 (m,
6H), 6.95-6.87 (m, 1H), 6.10 (m, 1H), 5.96 (d, J=2.7 Hz, 1H), 5.54
(d, J=5.3 Hz, 0.5H), 5.31 (d, J=4.2 Hz, 0.5H), 5.14 (s, 2H),
4.83-4.76 (m, 0.5H), 4.70-4.66 (m, 0.5H), 3.59 (s, 1.5H), 3.58 (s,
1.5H), 3.32-3.29 (m, 1H), 2.76 (d, J=16.3 Hz, 0.5H), 2.63 (d,
J=15.9 Hz, 0.5H), 2.37-2.14 (m, 2H), 2.02-1.77 (m, 4H), 1.75-1.59
(m, 1H); ESI MS m/z 454 [M+H].sup.+; HPLC (Method B) 98.5% (AUC),
t.sub.R=17.2 min.
Example 28
Preparation of
4-(Benzyloxy)-1-(11-isopropyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminoc-
yclohept[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
##STR00103##
[0301]
4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohep-
t[b]indol-3-yl)pyridin-2(1H)-one from (100 mg, 0.24 mmol) was
reacted with acetone (5 mL) following the procedure for Example 32
to provide the title compound (89 mg, 75%) as a white solid and as
a mixture of rotamers: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.71 (d, J=8.5 Hz, 0.3H), 7.68 (d, J=8.5 Hz, 0.7H), 7.61-7.59 (m,
1H), 7.48-7.46 (m, 3H), 7.43-7.42 (m, 2H), 7.41-7.36 (m, 1H),
7.09-7.08 (m, 1H), 6.35-6.32 (m, 1H), 6.16-6.15 (m, 1H), 5.40-5.38
(m, 1H), 4.91 (s, 2H), 4.71-4.53 (m, 1H), 3.72 (s, 3H), 3.56-3.47
(m, 1H), 3.42-3.32 (m, 1H), 3.21-3.02 (m, 1H), 2.61-2.41 (m, 2H),
2.32-2.18 (m, 1H), 2.15-1.98 (m, 1H), 1.53-1.49 (m, 2H), 1.49-1.43
(m, 2H), 1.32-1.26 (m, 2H); ESI MS m/z 454 [M+H].sup.+; HPLC
(Method B) 94.8% (AUC), t.sub.R=12.4 min.
Example 29
Preparation of
1-(11-Acetyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol--
3-yl)-4-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one
(Enantiomer A)
##STR00104##
[0303] To a solution of
4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-
-iminocyclohept[b]indol-3-yl)pyridin-2(11)-one (Enantiomer A) (60.0
mg, 0.130 mmol) in methylene chloride (4 mL) was added
K.sub.2CO.sub.3 (54.0 mg, 0.390 mmol) and acetyl chloride (18.0
.mu.L, 0.240 mmol). The reaction mixture was stirred at room
temperature for 1.5 h. The resulting suspension was filtered and
concentrated to dryness. Purification by preparative thin layer
chromatography (TLC) (silica gel, 90:9:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave the title
compound (46 mg, 75%) as a white solid and as a mixture of
rotamers: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.62 (d,
J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.67-7.64 (m, 1H), 7.61-7.54 (m,
2H), 7.39 (m, 1H), 6.94-6.91 (m, 1H), 6.12 (d, J=7.0 Hz, 1H), 5.97
(s, 1H), 5.56-5.54 (m, 0.4H), 5.40-5.30 (m, 0.6H), 5.20 (s, 2H),
4.90-4.60 (m, 1H), 3.59 (s, 1.2H), 3.58 (s, 1.8H), 2.78 (d, J=16.5
Hz, 0.4H), 2.65 (d, J=16.0 Hz, 0.6H), 2.36-2.15 (m, 2H), 2.03-1.80
(m, 5H), 1.72-1.60 (m, 1H); ESI MS m/z 473 [M+H].sup.+; HPLC
(Method A)>99% (AUC), t.sub.R=15.0 min.
Example 30
Preparation of
1-(11-Acetyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(-
benzyloxy)pyridin-2(1H)-one hydrochloride (Enantiomer A)
##STR00105##
[0305]
4-(Benzyloxy)-1-(5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-
-3-yl)pyridin-2(1H)-one hydrochloride (enantiomer A) (100 mg, 0.21
mmol) was reacted with acetyl chloride (22 mg, 0.27 mmol, 20 .mu.L)
following the procedure for Example 27 to provide the title
compound (67 mg, 73%) as a white solid and as a mixture of
rotamers: mp 140-170.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 9.49 (s, 0.3H), 9.14 (s, 0.7H), 7.43-7.26 (m, 8H),
6.93-6.91 (dd, J=8.2, 1.8 Hz, 0.7H), 6.85-6.83 (dd, J=8.2, 1.8 Hz,
0.3H), 6.09-6.05 (m, 2H), 5.58 (d, J=5.4 Hz, 0.3H), 5.10-5.06 (m,
2.7H), 5.01-4.58 (m, 0.7H), 4.48-4.30 (m, 0.3H), 3.39-3.35 (dd,
J=16.1, 4.3 Hz, 0.7H), 3.13-3.09 (dd, J=16.0, 4.0 Hz, 0.3H), 2.43
(d, J=16.0 Hz, 0.7H), 2.38 (d, J=16.0 Hz, 0.3H), 2.30-2.06 (m, 5H),
2.05-1.95 (m, 1H), 1.89-1.75 (m, 0.3H), 1.61-1.52 (m, 0.7H); ESI MS
m/z 440 [M+H].sup.+; HPLC (Method B)>99% (AUC), t.sub.R=16.2
min.
Example 31
Preparation of
4-(Benzyloxy)-1-(5,12-dimethyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cycl-
ooct[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
a)
4-(Benzyloxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooc-
t[b]indol-3-yl)pyridin-2(1H)-one
##STR00106##
[0307] tert-Butyl
3-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-6,7,8,9,10,11-hexahydro--
7,11-imino-5H-cyclooct[b]indole-12-carboxylate (400 mg, 0.761 mmol)
was stirred in TFA (2 mL) and CH.sub.2Cl.sub.2 (2 mL) for 1 h and
then concentrated. The residue was purified by Flash chromatography
(silica gel, CH.sub.2Cl.sub.2/(9:1 MeOH/NH.sub.4OH), 100:0 to
80:20) to provide the free base (227 mg, 70%) as a yellow oil: ESI
MS m/z 426 [M+H].sup.+.
b)
4-(Benzyloxy)-1-(5,12-dimethyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cy-
clooct[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
##STR00107##
[0309]
4-(Benzyloxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyc-
looct[b]indol-3-yl)pyridin-2(1H)-one (76 mg, 0.18 mmol) and 37%
aqueous formaldehyde (.about.0.5 mL) were dissolved in MeOH (2 mL)
and CH.sub.2Cl.sub.2 (2 mL) and stirred at room temperature for 0.5
h. Sodium triacetoxyborohydride (75 mg, 0.358 mmol) was then added,
and the reaction was stirred at room temperature for an additional
1 h. The mixture was concentrated, and the residue was partitioned
between CH.sub.2Cl.sub.2 and saturated Na.sub.2CO.sub.3 solution.
The organic phase was removed, and the aqueous phase was extracted
with CH.sub.2Cl.sub.2. The combined organics were dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness.
Purification by column chromatography (120 g ISCO column eluting
with methylene chloride and a methanol/ammonia mixture (10:1);
gradient 100% methylene chloride to 85% methylene chloride over 60
min) provided the free base of the title compound. The free base
was converted to the HCl salt using 2 N HCl in Et.sub.2O to provide
the title compound (69 mg, 81%) as a white solid: mp
161-180.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.96 (s, 1H), 7.60-7.51 (m, 3H), 7.49-7.35 (m, 5H), 6.99-6.96 (dd,
J=8.3, 1.8 Hz, 1H), 6.12-6.09 (dd, J=7.6, 2.7 Hz, 1H), 5.97 (d,
J=2.7 Hz, 1H), 5.15 (s, 2H), 5.02 (s, 1H), 3.98-3.93 (m, 1H), 3.70
(s, 3H), 3.43-3.35 (dd, J=18.3, 7.3 Hz, 1H), 3.07 (d, J=18.4 Hz,
1H), 2.65 (d, J=4.9 Hz, 3H), 2.36-2.16 (m, 2H), 1.86 (d, J=13.7 Hz,
1H), 1.74 (d, J=13.4 Hz, 1H), 1.42 (d, J=13.2 Hz, 1H), 1.26-1.14
(m, 1H); ESI MS m/z 440 [M+H].sup.+; HPLC (Method B) 98.9% (AUC),
t.sub.R=13.4 min.
Example 32
Preparation of
4-(Benzyloxy)-1-(12-ethyl-5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H--
cyclooct[b]indol-3-yl)pyridin-2(1H)-one hydrochloride
##STR00108##
[0311] Picoline-borane complex (57 mg, 0.54 mmol) was added to a
suspension of
4-(benzyloxy)-1-(5-methyl-6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[-
b]indol-3-yl)pyridin-2(1H)-one (76 mg, 0.18 mmol) and acetylaldhyde
(.about.0.2 mL) in 9:1 CH.sub.2Cl.sub.2/AcOH (10 mL) under N.sub.2,
and the resulting solution was stoppered and stirred for 2 h. The
solution was neutralized with saturated NaHCO.sub.3 solution, and
the phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by flash chromatography (12 g ISCO column eluting with
methylene chloride and a methanol/ammonia mixture (10:1); gradient
100% methylene chloride to 85% methylene chloride over 30 min)
provided the free base of the title compound. The free base was
converted to the HCl salt using 2 N HCl in Et.sub.2O to provide the
title compound (35 mg, 44%) as a white solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.46-10.26 (s, 1H), 7.59-7.57 (m, 2H), 7.51
(d, J=1.7 Hz, 1H), 7.48-7.46 (m, 2H), 7.44-7.41 (m, 2H), 7.39-7.37
(m, 1H), 6.98-6.96 (dd, J=8.3, 1.8 Hz, 1H), 6.16-6.09 (dd, J=7.6,
2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.15 (s, 3H), 4.15-4.01 (m,
1H), 3.69 (s, 3H), 3.40 (dd, J=18.2, 6.7 Hz, 1H), 3.09-3.04 (d,
J=18.2 Hz, 1H), 3.04-2.93 (m, 2H), 2.37-2.17 (m, 2H), 1.92-1.84 (d,
J=13.9 Hz, 1H), 1.75 (d, J=13.8 Hz, 1H), 1.49-1.41 (m, 1H),
1.32-1.19 (m, 4H); ESI MS m/z 454 [M+H].sup.+; HPLC (Method B)
93.8% (AUC), t.sub.R=13.6 min.
Example 33
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-ph-
enethylpiperazin-2-one dihydrochloride (Enantiomer B)
a) 4-Phenethylpiperazin-2-one
[0312] (CAS Registry Number 23099-72-1) (JP 43017188 to Irikura et
al., which is hereby incorporated by reference in its entirety)
##STR00109##
[0313] A suspension of (2-bromoethyl)benzene (4.10 mL, 30.0 mmol),
piperazin-2-one (3.00 g, 30.0 mmol) and K.sub.2CO.sub.3 (4.90 g,
36.0 mmol) in DMSO (60.0 mL) was stirred at 80.degree. C. for 5 h.
The reaction mixture was cooled to room temperature and filtered.
The filtrate was then washed with water (200 mL) and extracted with
methylene chloride (2.times.). The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The result yellow solid was then dissolved in 1 N HCl
(120 mL) and washed with methylene chloride. The aqueous layer was
separated, basified with 6 N NaOH, and extracted with methylene
chloride (3.times.). The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated. The residue was titrated
with hexanes and filtered. The filtered solid was dried under
reduced pressure to give the title compound (4.50 g, 74%) as an
off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.31-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.17 (brs, 1H), 3.40-3.37 (m,
2H), 3.23 (s, 2H), 2.83-2.79 (m, 2H), 2.73-2.67 (m, 4H).
b) 11-tert-Butyl 5-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-5,11-dicarbox-
ylate
##STR00110##
[0315] A solution of sodium hexamethyl disilazide in THF (130 mL,
1.0 M, 130 mmol) was added to a solution of tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (4.50 g, 11.9 mmol) in THF (60 mL) at -78.degree. C. The reaction
was stirred at -78.degree. C. for 40 min, and then (1S)-(+)-menthyl
chloroformate (5.00 mL, 23.7 mmol) was added dropwise over 5 min.
The reaction was stirred at -78.degree. C. for an additional 5 min.
Then the cooling bath was removed, and stirring continued for 2.5
h. The reaction mixture was treated with saturated aqueous
NH.sub.4Cl (60 mL) and extracted with ethyl acetate (3.times.). The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered and concentrated to dryness. Purification by flash column
chromatography (silica gel, ethyl acetate/hexanes, 0:100 to 30:70)
gave the title compound (5.00 g, 76%) as a yellow solid: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.36 (br s, 1H), 7.36 (d, J=8.0
Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 5.30-5.00 (m, 1H), 4.95-4.89 (m,
1H), 4.65-4.55 (m, 1H), 3.70-3.40 (m, 1H), 2.80 (d, J=17.5 Hz, 1H),
2.33-2.13 (m, 3H), 1.99-1.92 (m, 2H), 1.79-1.73 (m, 2H), 1.67-1.57
(m, 3H), 1.50-1.30 (br s, 9H), 1.21-1.10 (m, 2H), 1.10-0.81 (m,
10H).
c) (+)-tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (Enantiomer B)
##STR00111##
[0317] 11-tert-Butyl 5-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-5,11-dicarbox-
ylate (5.00 g, 9.00 mmol) was dissolved in hexanes (80 mL). After 3
days at -15.degree. C. the mixture was filtered and washed with
ice-cold hexanes to give a white crystal (1.6 g), which was then
dissolved in THF/MeOH/water (49 mL, 4:2:1). Lithium hydroxide
monohydrate (352 mg, 8.59 mmol) was added to the solution, and the
reaction was stirred at room temperature for 5 h. The reaction
mixture was neutralized with saturated aqueous NH.sub.4Cl and
extracted with ethyl acetate (3.times.). The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. Purification by flash column
chromatography (silica gel, ethyl acetate/hexanes, 0:100 to 30:70)
gave the title compound (1.10 g, 31%) as a white solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.76 (br s, 1H), 7.43 (br s, 1H),
7.36 (d, J=8.0 Hz, 1H), 7.20 (d, J=6.5 Hz, 1H), 5.30-5.10 (m, 1H),
4.70-4.50 (m, 1H), 3.50-3.30 (m, 1H), 2.46 (d, J=15.5 Hz, 1H),
2.33-2.26 (m, 1H), 2.21-2.13 (m, 1H), 1.96-1.91 (m, 1H), 1.66-1.60
(m, 1H), 1.50-1.30 (m, 9H); HPLC (Method A) 97.8% (AUC),
t.sub.R=23.0 min; Chiral HPLC (Chiralpak OJ, 260 nm, 80:20:0.1
reagent alcohol/heptane/trifluoroacetic acid) 94.8% (AUC),
t.sub.R=23.8 min; [.alpha.].sup.20.sub.D+68.2.degree. (c 0.2,
CDCl.sub.3).
d) (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (Enantiomer B)
##STR00112##
[0319] Sodium hydride (60% weight dispersion in mineral oil, 135
mg, 3.40 mmol) and methyl iodide (482 mg, 210 .mu.L, 3.40 mmol)
were added to a solution of (+)-tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (enantiomer B) (1.10 g, 2.80 mmol) in DMF (8 mL) at 0.degree. C.
under N.sub.2. The reaction was allowed to warm to room temperature
for 3.5 h. The mixture was quenched with H.sub.2O at 0.degree. C.,
and a solid precipitated out of solution. The solids were filtered
off to provide the title compound (1.10 g, 100%) as a yellow solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 6.52 (s, 1H), 6.47 (d,
J=8.5 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 4.38-4.25 (m, 1H), 3.82-3.73
(m, 1H), 2.67 (s, 3H), 2.53-2.39 (m, 1H), 1.60-1.56 (m, 1H),
1.45-1.37 (m, 1H), 1.32-1.24 (m, 1H), 1.06-1.01 (m, 1H), 0.76-0.70
(m, 1H), 0.55-0.46 (m, 9H).
e) tert-Butyl
5-methyl-3-(2-oxo-4-phenethylpiperazin-1-yl)-5,6,7,8,9,10-hexahydro-7,10--
iminocyclohept[b]indole-11-carboxylate (Enantiomer B)
##STR00113##
[0321] (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer B) (150 mg, 0.380 mmol) and
4-phenethylpiperazin-2-one (86.0 mg, 0.420 mmol), CuI (145 mg,
0.760 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (12.0
.mu.L, 0.080 mmol) and Cs.sub.2CO.sub.3 (248 mg, 0.760 mmol) in
dioxane (5 mL) were reacted following the procedure for Example 2
(step c) to provide the title compound (82.0 mg, 42%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.51 (d, J=8.0 Hz,
1H), 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 7.18 (d, J=1.5 Hz, 1H),
7.00-6.90 (m, 1H), 5.30-5.17 (m, 1H), 4.71-4.59 (m, 1H), 3.75 (br
s, 2H), 3.55 (s, 3H), 3.44 (br s, 2H), 3.44-3.30 (m, 1H), 2.92-2.85
(m, 4H), 2.77-2.73 (m, 2H), 2.47 (d, J=15.5 Hz, 1H), 2.40-2.20 (m,
1H), 2.20-2.12 (m, 1H), 1.94-1.90 (m, 1H), 1.70-1.50 (m, 1H),
1.50-1.30 (m, 9H).
f)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
phenethylpiperazin-2-one dihydrochloride (Enantiomer B)
##STR00114##
[0323] tert-Butyl
5-methyl-3-(2-oxo-4-phenethylpiperazin-1-yl)-5,6,7,8,9,10-hexahydro-7,10--
iminocyclohept[b]indole-11-carboxylate (enantiomer B) (82.0 mg,
0.160 mmol) was deprotected and converted to the hydrochloride salt
according to the procedure for Example 2 (step d) to provide the
title compound (33.0 mg, 33%) as a yellow solid. Free Base: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 7.47 (d, J=8.5 Hz, 1H), 7.33-7.30
(m, 2H), 7.26-7.23 (m, 3H), 7.19 (s, 1H), 6.96 (dd, J=8.0, 1.5 Hz,
1H), 4.70-4.69 (m, 1H), 4.21 (m, 1H), 3.76-3.73 (m, 2H), 3.44 (s,
2H), 3.40 (s, 3H), 3.25 (dd, J=16.0, 4.0 Hz, 1H), 2.92-2.86 (m,
4H), 2.77-2.74 (m, 2H), 2.52 (d, J=16.5 Hz, 1H), 2.31-2.19 (m, 2H),
2.03-2.00 (m, 1H), 1.60-1.55 (m, 1H); HPLC (Method A) 98.0% (AUC),
t.sub.R=10.1 min. HCl salt: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.62 (d, J=8.5 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.40-7.35
(m, 4H), 7.32-7.28 (m, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 5.22 (d,
J=5.5 Hz, 1H), 4.55-4.52 (m, 1H), 4.30-3.80 (m, 6H), 3.70 (s, 3H),
3.63-3.59 (m, 2H), 3.52-3.47 (m, 1H), 3.22-3.18 (m, 2H), 3.08-3.04
(m, 1H), 2.47-2.35 (m, 2H), 2.29-2.24 (m, 1H), 2.00-1.94 (m, 1H);
ESI MS m/z 415 [M+H].sup.+; HPLC (Method A) 98.6% (AUC),
t.sub.R=10.1 min.
Example 34
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-ph-
enethylpiperazin-2-one dihydrochloride (Enantiomer A)
a) 11-tert-Butyl
5-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)3-bromo-5,6,7,8,9,10-hexahyd-
ro-7,10-iminocyclohept[b]indole-5,11-dicarboxylate
##STR00115##
[0325] Sodium hexamethyl disilazide in THF (2.90 mL, 1.0 M, 2.80
mmol), (1R)-(-)-menthyl chloroformate (1.10 mL, 5.20 mmol) and
tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (1.00 g, 2.60 mmol) in THF (15 mL) were reacted following the
procedure for Example 33 (step b) to provide the title compound
(1.20 mg, 85%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.36 (br s, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.5 Hz,
1H), 5.30-5.00 (m, 1H), 4.95-4.89 (m, 1H), 4.65-4.55 (m, 1H),
3.70-3.40 (m, 1H), 2.80 (d, J=17.5 Hz, 1H), 2.40-2.10 (m, 3H),
2.10-1.90 (m, 2H), 1.79-1.73 (m, 2H), 1.67-1.57 (m, 3H), 1.50-1.30
(br s, 9H), 1.21-1.10 (m, 2H), 1.10-0.81 (m, 10H).
b) (-)-tert-Butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (Enantiomer A)
##STR00116##
[0327] Crystallization of 11-tert-Butyl
5-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)3-bromo-5,6,7,8,9,10-hexahyd-
ro-7,10-iminocyclohept[b]indole-5,11-dicarboxylate (1.20 g, 2.20
mmol) in hexanes (20 mL) was performed following the procedure for
Example 33 (step c) to provide a white crystal (229 mg), which was
then dissolved in THF/MeOH/water (7 mL, 4:2:1). The resulting
solution was reacted with lithium hydroxide monohydrate (50.0 mg,
1.20 mmol) following the procedure for Example 33 (step c) to give
the title compound (155 mg, 16%) as a white solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.95 (br s, 1H), 7.41 (br s, 1H), 7.34 (d,
J=7.5 Hz, 1H), 7.18 (br s, 1H), 5.30-5.10 (m, 1H), 4.70-4.50 (m,
1H), 3.50-3.30 (m, 1H), 2.46 (d, J=16.0 Hz, 1H), 2.40-2.20 (m, 1H),
2.20-2.10 (m, 1H), 1.96-1.91 (m, 1H), 1.70-1.60 (m, 1H), 1.50-1.30
(m, 9H); HPLC (Method A) 99.4% (AUC), t.sub.R=23.0 min; Chiral HPLC
(Chiralpak OJ, 260 nm, 80:20:0.1 reagent
alcohol/heptane/trifluoroacetic acid) 100% (AUC), t.sub.R=22.7
min.
c) (-)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (Enantiomer A)
##STR00117##
[0329] Sodium hydride (60% weight dispersion in mineral oil, 27.0
mg, 0.680 mmol), methyl iodide (96.5 mg, 42.0 .mu.L, 0.680 mmol)
and (-)-tert-butyl
3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylat-
e (213 mg, 0.560 mmol) in DMF (3 mL) were reacted following the
procedure for Example 33 (step d) to provide the title compound
(144 mg, 66%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 6.52 (s, 1H), 6.48 (d, J=8.5 Hz, 1H), 6.30 (d, J=7.5 Hz,
1H), 4.42-4.25 (m, 1H), 3.82-3.73 (m, 1H), 2.67 (s, 3H), 2.53-2.36
(m, 1H), 1.60-1.56 (m, 1H), 1.42-1.38 (m, 1H), 1.32-1.24 (m, 1H),
1.06-1.01 (m, 1H), 0.76-0.70 (m, 1H), 0.55-0.46 (m, 9H).
d)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
phenethylpiperazin-2-one dihydrochloride (Enantiomer A)
##STR00118##
[0331] (-)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer A) (70.0 mg, 0.180 mmol),
4-phenethylpiperazin-2-one (40.0 mg, 0.200 mmol), CuI (69.0 mg,
0.360 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (5.60
.mu.L, 0.0400 mmol) and Cs.sub.2CO.sub.3 (117 mg, 0.360 mmol) in
dioxane (5 mL) were reacted following the procedure for Example 2
(step c) to give tert-butyl
5-methyl-3-(2-oxo-4-phenethylpiperazin-1-yl)-5,6,7,8,9,10-hexahydro-7,10--
iminocyclohept[b]indole-11-carboxylate (580 mg) as a yellow solid.
The yellow solid was deprotected and converted to the hydrochloride
salt according to the procedure for Example 2 (step d) to provide
the title compound (12.8 mg, 15%) as a yellow solid. Free Base:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.47 (d, J=8.5 Hz, 1H),
7.33-7.30 (m, 2H), 7.26-7.23 (m, 3H), 7.19 (d, J=1.5 Hz, 1H), 6.96
(dd, J=8.0, 1.5 Hz, 1H), 4.70-4.69 (m, 1H), 4.21-4.40 (m, 1H),
3.76-3.73 (m, 2H), 3.44 (s, 2H), 3.43 (s, 3H), 3.42 (dd, J=16.0,
4.0 Hz, 1H), 2.92-2.86 (m, 4H), 2.77-2.74 (m, 2H), 2.56 (d, J=16.0
Hz, 1H), 2.40-2.20 (m, 2H), 2.08-2.04 (m, 1H), 1.63-1.60 (m, 1H);
HPLC (Method A) 96.0% (AUC), t.sub.R=10.1 min. HCl salt: .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.64 (d, J=8.5 Hz, 1H), 7.44 (d,
J=1.5 Hz, 1H), 7.40-7.35 (m, 4H), 7.32-7.28 (m, 1H), 7.08 (dd,
J=8.0, 1.5 Hz, 1H), 5.22 (d, J=5.5 Hz, 1H), 4.55-4.52 (m, 1H),
4.30-3.80 (m, 6H), 3.70 (s, 3H), 3.62-3.58 (m, 2H), 3.50 (dd,
J=17.5, 4.5 Hz, 1H), 3.21-3.16 (m, 2H), 3.06 (d, J=17.0 Hz, 1H),
2.49-2.34 (m, 2H), 2.29-2.24 (m, 1H), 2.00-1.97 (m, 1H); ESI MS m/z
415 [M+H].sup.+; HPLC (Method A) 97.8% (AUC), t.sub.R=10.0 min.
Example 35
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-
-methylpyridin-3-yl)-pyridin-2(1H)-one hydrochloride (Enantiomer
B)
a) 2'-Methoxy-6-methyl-3,4'-bipyridine
[0332] (CAS Registry Number 1173156-60-9) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00119##
[0333]
2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(3.5 g, 16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol)
were reacted according to Example 3 (step a) to provide the title
compound (2.1 g, 98%) as a brown solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.75 (d, J=2.1 Hz, 1H), 8.23 (d, J=5.4 Hz, 1H),
7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1, 1H), 7.08 (dd, J=5.4,
1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H), 2.61 (s, 3H).
b) 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one
[0334] (CAS Registry Number 1173156-63-2) (WO 2009/089482 to Guzzo
et al., which is hereby incorporated by reference in its
entirety)
##STR00120##
[0335] 2'-Methoxy-6-methyl-3,4'-bipyridine (2.1 g, 10.4 mmol) was
reacted according to Example 3 (step b) to provide the title
compound (1.36 mg, 68%) as a white solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.65 (s, 1H) 8.78 (d, J=2.1 Hz, 1H), 8.01
(dd, J=8.1, 2.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H), 7.36 (d, J=8.1,
1H), 6.66 (d, J=1.4 Hz, 1H), 6.55 (dd, J=6.9, 1.8 Hz, 1H), 2.51 (s,
3H).
a) tert-Butyl
5-methyl-3-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10--
hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (Enantiomer
B)
##STR00121##
[0337] (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer B) (150 mg, 0.380 mmol),
4-(6-methylpyridin-3-yl)pyridin-2(1H)-one (85.0 mg, 0.460 mmol),
CuI (108 mg, 0.570 mmol), 8-hydroxyquinoline (11.0 mg, 80.0
.mu.mol) and Cs.sub.2CO.sub.3 (248 mg, 0.760 mmol) in DMSO (5 mL)
were reacted following the procedure for Example 2 (step c) to
provide the title compound (32.0 mg, 17%) as a yellow solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.79 (d, J=2.0 Hz, 1H),
7.83 (dd, J=8.5, 2.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.52 (br s,
1H), 7.33 (d, J=1.5 Hz, 1H), 7.29-7.22 (m, 1H), 7.06 (br s, 1H),
6.90 (d, J=1.5 Hz, 1H), 6.49 (d, J=7.0 Hz, 1H), 5.40-5.20 (m, 1H),
4.80-4.60 (m, 1H), 3.60 (s, 3H), 3.50-3.30 (m, 1H), 2.64 (s, 3H),
2.51 (d, J=15.5 Hz, 1H), 2.40-2.30 (m, 1H), 2.23-2.15 (m, 1H),
1.97-1.92 (m, 1H), 1.70-1.50 (m, 1H), 1.50-1.30 (m, 9H); HPLC
(Method A) 98.0% (AUC), t.sub.R=14.3 min.
b)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(6-methylpyridin-3-yl)pyridin-2(1H)-one hydrochloride (Enantiomer
B)
##STR00122##
[0339] tert-Butyl
5-methyl-3-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-5,6,7,8,9,10--
hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate (Enantiomer
B) (32.0 mg, 0.064 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (21.0 mg, 81%) as a yellow solid:
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.15 (d, J=2.0 Hz, 1H),
8.85 (dd, J=8.5, 2.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.89 (d,
J=7.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.15
(dd, J=8.0, 1.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.90 (dd, J=7.0,
2.0 Hz, 1H), 5.26 (d, J=5.0 Hz, 1H), 4.58-4.56 (m, 1H), 3.73 (s,
3H), 3.52 (dd, J=17.0, 4.5 Hz, 1H), 3.10 (dd, J=17.0, 1.0 Hz, 1H),
2.87 (s, 3H), 2.51-2.36 (m, 2H), 2.32-2.27 (m, 1H), 2.03-1.99 (m,
1H); ESI MS m/z 397 [M+H].sup.+; HPLC (Method A) 96.7% (AUC),
t.sub.R=9.2 min.
Example 36
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-
-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer B)
a) tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(Enantiomer B)
##STR00123##
[0341] (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer B) (150 mg, 0.380 mmol),
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (110 mg, 0.460
mmol), CuI (108 mg, 0.570 mmol), 8-hydroxyquinoline (11.0 mg,
0.0800 mmol) and Cs.sub.2CO.sub.3 (248 mg, 0.760 mmol) in DMSO (5
mL) were reacted following the procedure for Example 2 (step c) to
provide the title compound (68.0 mg, 33%) as a yellow solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.99 (d, J=1.5 Hz, 1H),
8.10 (dd, J=8.0, 1.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.61 (d,
J=8.5 Hz, 2H), 7.33 (d, J=1.5 Hz, 1H), 7.06 (br s, 1H), 6.93 (d,
J=1.5 Hz, 1H), 6.48 (dd, J=7.0, 2.0 Hz, 1H), 5.40-5.30 (m, 1H),
4.80-4.60 (m, 1H), 3.61 (s, 3H), 3.49-3.34 (m, 1H), 2.53-2.49 (d,
J=16.0 Hz, 1H), 2.40-2.30 (m, 1H), 2.24-2.16 (m, 1H), 1.97-1.93 (m,
1H), 1.70-1.50 (m, 1H), 1.50-1.30 (m, 9H); HPLC (Method A) 97.8%
(AUC), t.sub.R=21.8 min.
b)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer B)
##STR00124##
[0343] tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(enantiomer B) (68.0 mg, 0.124 mmol) was deprotected and converted
to the hydrochloride salt according to the procedure for Example 2
(step d) to provide the title compound (50.0 mg, 86%) as a yellow
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.10 (s, 1H), 8.41
(d, J=8.0 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.84 (d, J=7.0 Hz, 1H),
7.71 (d, J=8.0 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H), 7.15 (dd, J=8.0,
1.5 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 6.89 (dd, J=7.0, 1.5 Hz, 1H),
5.26 (d, J=5.0 Hz, 1H), 4.58-4.55 (m, 1H), 3.73 (s, 3H), 3.52 (dd,
J=17.5, 4.5 Hz, 1H), 3.10 (d, J=17.0, 1H), 2.51-2.36 (m, 2H),
2.32-2.27 (m, 1H), 2.03-1.99 (m, 1H); ESI MS m/z 451 [M+H].sup.+;
HPLC (Method C) 98.5% (AUC), t.sub.R=13.9 min.
Example 37
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-
-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer A)
a) tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(Enantiomer A)
##STR00125##
[0345] (-)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer A) (71.0 mg, 0.180 mmol),
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (52.0 mg,
0.220 mmol), CuI (51.0 mg, 0.270 mmol), 8-hydroxyquinoline (5.20
mg, 0.040 mmol) and Cs.sub.2CO.sub.3 (117 mg, 0.360 mmol) in DMSO
(5 mL) were reacted following the procedure for Example 2 (step c)
to provide the title compound (19 mg, 19%) as a yellow solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.99 (s, 1H), 8.10 (d,
J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.47
(s, 1H), 7.06 (br s, 1H), 6.94 (s, 1H), 6.48 (d, J=6.5 Hz, 1H),
5.40-5.20 (m, 1H), 4.80-4.60 (m, 1H), 3.61 (s, 3H), 3.57-3.35 (m,
1H), 2.53-2.49 (d, J=16.0 Hz, 1H), 2.40-2.30 (m, 1H), 2.24-2.16 (m,
1H), 1.97-1.93 (m, 1H), 1.62-1.57 (m, 1H), 1.50-1.30 (m, 9H); HPLC
(Method A) 95.8% (AUC), t.sub.R=21.8 min.
b)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
(Enantiomer A)
##STR00126##
[0347] tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,-
6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(enantiomer A) (19.0 mg, 34.5 .mu.mol) was deprotected and
converted to the hydrochloride salt according to the procedure for
Example 2 (step d) to provide the title compound (13 mg, 89%) as a
yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.10 (d,
J=2.0 Hz, 1H), 8.41 (dd, J=8.0, 2.0 Hz, 1H), 7.97 (d, J=8.5 Hz,
1H), 7.84 (d, J=7.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.55 (d, J=1.5
Hz, 1H), 7.15 (dd, J=8.0, 1.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.89
(dd, J=7.0, 2.0 Hz, 1H), 5.26 (d, J=5.0 Hz, 1H), 4.57-4.54 (m, 1H),
3.73 (s, 3H), 3.52 (dd, J=17.5, 5.0 Hz, 1H), 3.10 (dd, J=17.0, 1.0
Hz, 1H), 2.51-2.36 (m, 2H), 2.32-2.28 (m, 1H), 2.04-2.01 (m, 1H);
ESI MS m/z 451 [M+H].sup.+; HPLC (Method C) 97.9% (AUC),
t.sub.R=13.8 min.
Example 38
Preparation of
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-((-
6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one
hydrochloride (Enantiomer B)
a) tert-Butyl
5-methyl-3-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(Enantiomer B)
##STR00127##
[0349] (+)-tert-Butyl
3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-c-
arboxylate (enantiomer B) (150 mg, 0.380 mmol),
4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (124
mg, 0.460 mmol), CuI (108 mg, 0.570 mmol), 8-hydroxyquinoline (11.0
mg, 0.080 mmol) and Cs.sub.2CO.sub.3 (248 mg, 0.760 mmol) in DMSO
(5 mL) were reacted following the procedure for Example 2 (step c)
to provide the title compound (22.0 mg, 10%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.81 (s, 1H), 7.96 (d,
J=8.4 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.35
(d, J=6.9 Hz, 1H), 7.25 (s, 1H), 6.99 (br s, 1H), 6.07-6.03 (m,
2H), 5.40-5.20 (m, 1H), 5.16 (s, 2H), 4.80-4.60 (m, 1H), 3.59 (s,
3H), 3.50-3.20 (m, 1H), 2.53-2.47 (d, J=16.2 Hz, 1H), 2.40-2.10 (m,
2H), 1.97-1.90 (m, 1H), 1.70-1.50 (m, 1H), 1.50-1.30 (m, 9H).
b)
1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4--
((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one
hydrochloride (Enantiomer B)
##STR00128##
[0351] tert-Butyl
5-methyl-3-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-(2H)-
-yl)-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate
(enantiomer B) (25.0 mg, 43.1 .mu.mol) was deprotected and
converted to the hydrochloride salt according to the procedure for
Example 2 (step d) to provide the title compound (18.0 mg, 87%) as
a yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.84 (s,
1H), 8.16 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.5
Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.07 (dd,
J=8.5, 2.0 Hz, 1H), 6.35 (dd, J=8.0, 3.0 Hz, 1H), 6.17 (d, J=2.5
Hz, 1H), 5.36 (s, 2H), 5.24 (d, J=5.5 Hz, 1H), 4.56-4.53 (m, 1H),
3.70 (s, 3H), 3.50 (dd, J=17.0, 4.5 Hz, 1H), 3.08 (dd, J=17.5, 1.5
Hz, 1H), 2.48-2.36 (m, 2H), 2.31-2.26 (m, 1H), 2.02-2.00 (m, 1H);
ESI MS m/z 481 [M+H].sup.+; HPLC (Method A) 96.8% (AUC),
t.sub.R=13.1 min.
Example 39
Preparation of
4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5-
]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one hydrochloride
a) 1-Chloroethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate
[0352] (CAS Registry Number 799283-74-2) (WO 2004/100946 to
Borcherding et al., which is hereby incorporated by reference in
its entirety)
##STR00129##
[0353] To a solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one
(30.0 g, 210 mmol) in 1,2-dichloroethane (100 mL) was added
1-chloroethyl chloroformate (25.8 mL, 240 mmol). The reaction
mixture was heated to reflux for 18 h. The mixture was cooled to
room temperature and filtered. The filtrate was concentrated and
purified by flash column chromatography (silica gel, hexanes/ethyl
acetate, 100:0 to 80:20) to give the title compound (40.2 g, 83%)
as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
6.67-3.63 (m, 1H), 4.65-4.57 (m, 2H), 2.83-2.56 (m, 2H), 2.42 (d,
J=5.5 Hz, 1H), 2.38 (d, J=5.5 Hz, 1H), 2.30-2.10 (m, 2H), 1.85 (d,
J=6.0 Hz, 3H), 1.80-1.70 (m, 2H).
b) 2-Bromo-6-(1-methylhydrazinyl)pyridine
##STR00130##
[0355] A suspension of 2,6-dibromopyridine (10.0 g, 42.0 mmol) in
anhydrous methylhydrazine (10 mL) was heated at 100.degree. C. for
2 h. The mixture was cooled to room temperature and washed with
water (3.times.20 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 80:20) gave the title compound (5.70 g, 66%) as
white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.30-7.26
(dd, J=8.5, 7.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.0 Hz,
1H), 4.03 (br s, 2H), 3.36 (s, 3H).
c) 1-Chloroethyl
3-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)-8-azabicyclo[3.2.1]octane-8-
-carboxylate
##STR00131##
[0357] A solution of 2-bromo-6-(1-methylhydrazinyl)pyridine (1.60
g, 7.90 mmol), 1-chloroethyl
3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 7.90 mmol)
and p-toluenesulphonic acid (300 mg, 1.60 mmol) in toluene (50 mL)
was heated under reflux, with water removal (azeotrope), for 3 h.
The mixture was cooled to room temperature and concentrated. The
residue was purified by flash column chromatography (silica gel,
0%-100% solvent mixture B in methylene chloride; solvent mixture
B=80:18:2 methylene chloride/methanol/concentrated ammonium
hydroxide) to give the title compound (676 mg, 28%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.31 (t, J=7.5 Hz,
1H), 6.88 (d, J=7.5 Hz, 1H), 6.68-6.65 (m, 1H), 6.62 (d, J=8.0 Hz,
1H), 4.63-4.40 (m, 3H), 3.17 (s, 3H), 2.93-2.90 (m, 1H), 265-2.62
(m, 1H), 2.42-2.37 (dd, J=16.0, 6.0 Hz, 1H), 2.13-2.00 (m, 3H),
1.85 (d, J=6.0 Hz, 3H), 1.80-1.73 (m, 1H).
d)
4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4-
,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one hydrochloride
##STR00132##
[0359] A mixture of 1-chloroethyl
3-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)-8-azabicyclo[3.2.1]octane-8-
-carboxylate (676 mg, 1.57 mmol) and polyphosphoric acid (2 mL) was
heated at 180.degree. C. for 25 min. After cooling to room
temperature, the reaction mixture was basified with 6N NaOH and
extracted with methylene chloride (3.times.). The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. The residue was purified by flash column
chromatography (silica gel, 0%-100% solvent mixture B in methylene
chloride; solvent mixture B=80:18:2 methylene
chloride/methanol/concentrated ammonium hydroxide) to give
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine (185 mg) as a brown oil.
[0360]
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]py-
rrolo[2,3-b]pyridine (185 mg, 0.640 mmol),
4-(benzyloxy)pyridin-2(1H)-one (154 mg, 0.760 mmol), CuI (183 mg,
0.960 mmol), 8-hydroxyquinoline (18.6 mg, 0.130 mmol) and
Cs.sub.2CO.sub.3 (417 mg, 1.20 mmol) in DMSO (5 mL) were reacted
following the procedure for Example 2 (steps c and d) to provide
the free base of the title compound (8.0 mg) as a yellow solid.
1.25 M HCl in methanol (0.02 mL, 0.03 mmol) was added to a solution
of the solid in MeOH (3 mL). Concentration under vacuum provided
the title compound (6.5 mg, 3%) as a yellow solid. Free Base:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.85 (d, J=8.0 Hz, 1H),
7.67 (d, J=7.5 Hz, 1H), 7.44-7.33 (m, 7H), 6.11-6.05 (m, 1H), 6.05
(d, J=2.5 Hz, 1H), 5.06 (s, 2H), 4.75 (d, J=4.5 Hz, 1H), 4.30-4.20
(m, 1H), 3.66 (s, 3H), 3.44-3.40 (dd, J=16.5, 4.5 Hz, 1H), 2.63 (d,
J=16.5 Hz, 1H), 2.36-2.26 (m, 2H), 2.08-2.03 (m, 1H), 1.69-1.65 (m,
1H); HPLC (Method D) 97.1% (AUC), t.sub.R=7.2 min. HCl salt:
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.10 (d, J=8.0 Hz, 1H),
7.82 (d, J=7.5 Hz, 1H), 7.48-7.35 (m, 6H), 6.37 (dd, J=7.5, 2.5 Hz,
1H), 6.15 (d, J=2.5 Hz, 1H), 5.26 (d, J=5.5 Hz, 1H), 5.21 (s, 2H),
4.58-4.55 (m, 1H), 3.75 (s, 3H), 3.54 (dd, J=17.5, 4.5 Hz, 1H),
3.15-3.11 (dd, J=17.5, 1.0 Hz, 1H), 2.51-2.36 (m, 2H), 2.33-2.28
(m, 1H), 2.04-2.02 (m, 1H); ESI MS m/z 413 [M+H].sup.+; HPLC
(Method D) 97.6% (AUC), t.sub.R=10.2 min.
Example 40
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(11-methyl-5,6,7,8,9,10-hexahydro-5,9-
-imino-11H-cycloocta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a) tert-Butyl
3-(2-(6-bromopyridin-2-yl)hydrazono)-9-azabicyclo[3.3.1]nonane-9-carboxyl-
ate
##STR00133##
[0362] 2-Bromo-6-hydrazinylpyridine (393 mg, 2.09 mmol) and
tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg,
2.09 mmol) were heated at reflux in EtOH (5 mL) for 16 h and the
mixture concentrated to provide the title compound (855 mg, 100%)
as a yellow solid: ESI MS m/z 409 [M+H].sup.+.
b) tert-Butyl
3-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)-9-azabicyclo[3.3.1]nonane-9-
-carboxylate
##STR00134##
[0364] tert-Butyl
3-(2-(6-bromopyridin-2-yl)hydrazono)-9-azabicyclo[3.3.1]nonane-9-carboxyl-
ate (609 mg, 1.49 mmol) was dissolved in DMF, and NaH (60%, 65 mg,
1.63 mmol) was added. After 30 min, MeI (232 mg, 1.63 mmol, 102
.mu.L) was added, and stirring continued for 30 min. The mixture
was poured into water and extracted with ethyl acetate. The ethyl
acetate was concentrated to provide the crude product (655 mg,
>100%) as a red oil: ESI MS m/z 423 [M+H].sup.+.
c) tert-Butyl
2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-5,9-imino-11H-cycloocta[4,5]pyrr-
olo[2,3-b]pyridine-12-carboxylate
##STR00135##
[0366] tert-Butyl
3-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)-9-azabicyclo[3.3.1]nonane-9-
-carboxylate (655 mg, 1.49 mmol, estimated) was combined with
p-toluenesulphonic acid (579 mg, 3.14 mmol) and heated to
160.degree. C. for 15 minutes. The mixture was allowed to cool and
isopropanol (20 mL), water (10 mL), potassium carbonate (1.03 g,
7.45 mmol), and di-tert-butyl dicarbonate (0.65 g, 4.9 mmol) were
added. After stirring for 16 h, the mixture was partitioned between
methylene chloride and water. The organic layer was removed, dried
and concentrated, and the residue was purified by column
chromatography eluting with ethyl acetate/hexanes (1:4) to provide
the title compound (300 mg, 50%) as a orange oil: ESI MS m/z 406
[M+H].sup.+.
d) tert-Butyl
2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-11-methyl-5,6-
,7,8,9,10-hexahydro-5,9-imino-11H-cycloocta[4,5]pyrrolo[2,3-b]pyridine-12--
carboxylate
##STR00136##
[0368] tert-Butyl
2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-5,9-imino-11H-cycloocta[4,5]pyrr-
olo[2,3-b]pyridine-12-carboxylate (150 mg, 0369 mmol) and
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (73 mg, 0.33
mmol) were reacted following the procedure for Example 2 (step c)
to provide the title compound (106 mg, 52%) as a yellow oil: ESI MS
m/z 546 [M+H].sup.+.
e)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(11-methyl-5,6,7,8,9,10-hexahydro-5-
,9-imino-11H-cycloocta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00137##
[0370] tert-Butyl
2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-11-methyl-5,6-
,7,8,9,10-hexahydro-5,9-imino-11H-cycloocta[4,5]pyrrolo[2,3-b]pyridine-12--
carboxylate (106 mg, 0.194 mmol) was reacted following the
procedure for Example 2 (step d) to provide the title compound (64
mg, 69%) as a white solid: mp 170-180.degree. C. deliquesc; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 9.61 (d, J=11.3 Hz, 1H), 9.13
(d, J=10.7 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H),
7.86-7.79 (m, 2H), 7.68-7.63 (dd, J=8.6, 4.5 Hz, 1H), 7.33 (d,
J=8.2 Hz, 1H), 6.22-6.18 (dd, J=7.7, 2.6 Hz, 1H), 6.00 (d, J=2.6
Hz, 1H), 5.23 (s, 2H), 5.03 (s, 1H), 4.11-3.96 (m, 1H), 3.73 (s,
3H), 3.49-3.39 (dd, J=18.3, 7.5 Hz, 1H), 3.16 (d, J=18.2 Hz, 1H),
2.16-1.94 (m, 2H), 1.82 (d, J=13.9 Hz, 1H), 1.72 (d, J=13.9 Hz,
1H), 1.49-1.45 (m, 1H), 1.34-1.25 (m, 1H); ESI MS m/z 446
[M+H].sup.+; HPLC (Method B)>99% (AUC), t.sub.R=11.7 min.
Example 41
Preparation of
4-(Benzyloxy)-1-(11-methyl-5,6,7,8,9,10-hexahydro-5,9-imino-11H-cycloocta-
[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-11-methyl-5,6,7,8,9,10-hexahydro--
5,9-imino-11H-cycloocta[4,5]pyrrolo[2,3-b]pyridine-12-carboxylate
##STR00138##
[0372] tert-Butyl
2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-5,9-imino-11H-cycloocta[4,5]pyrr-
olo[2,3-b]pyridine-12-carboxylate (150 mg, 0.369 mmol) and
4-(benzyloxy)pyridin-2(1H)-one (67 mg, 0.33 mmol) were reacted
following the procedure for Example 2 (step c) to provide the title
compound (90 mg, 43%) as a yellow oil: ESI MS m/z 527
[M+H].sup.+.
b)
4-(Benzyloxy)-1-(11-methyl-5,6,7,8,9,10-hexahydro-5,9-imino-11H-cyclooc-
ta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00139##
[0374] tert-Butyl
2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-11-methyl-5,6,7,8,9,10-hexahydro--
5,9-imino-11H-cycloocta[4,5]pyrrolo[2,3-b]pyridine-12-carboxylate
(90 mg, 0171 mmol) was reacted following the procedure for Example
2 (step d) to provide the title compound (60 mg, 76%) as a white
solid: mp 191-206.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.52 (d, J=10.6 Hz, 1H), 9.10 (d, J=10.5 Hz, 1H), 8.09 (d,
J=8.3 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.49 (m, 6H), 6.19-6.15 (dd,
J=7.6, 2.7 Hz, 1H), 6.00 (dd, J=2.7 Hz, 1H), 5.17 (s, 2H), 5.06 (s,
1H), 4.18-4.00 (m, 1H), 3.73 (s, 3H), 3.44-3.36 (dd, J=18.3, 7.4
Hz, 1H), 3.09 (d, J=18.1 Hz, 1H), 2.15-2.00 (m, 2H), 1.83 (d,
J=13.3 Hz, 1H), 1.72 (d, J=13.4 Hz, 1H), 1.49-1.45 (m, 1H),
1.34-1.14 (m, 1H); ESI MS m/z 427 [M+H].sup.+; HPLC (Method
B)>99% (AUC), t.sub.R=13.1 min.
Example 42
Preparation of
4-(Benzyloxy)-1-(10,11-dimethyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohept-
a[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a)
2-bromo-10,11-dimethyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]p-
yrrolo[2,3-b]pyridine
##STR00140##
[0376] 2-Bromo-6-(1-methylhydrazinyl)pyridine (202 mg, 1.00 mmol),
8-methyl-8-azabicyclo[3.2.1]octan-3-one (139 mg, 1.00 mmol) and
p-toluenesulphonic acid (19.0 mg, 100 .mu.mol) in toluene (10 mL)
were reacted following the procedure for Example 39 (step c). The
result crude product was then reacted with polyphosphoric acid
(3.23 g) following the procedure for Example 39 (step d) to give
the title compound (33.0 mg, 11%) as brown solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.58 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.5 Hz,
1H), 4.15 (d, J=5.0 Hz, 1H), 3.68 (s, 3H), 3.67-3.64 (m, 1H),
3.45-3.43 (m, 1H), 3.19-3.15 (dd, J=16.0, 4.5 Hz, 1H), 2.38 (s,
3H), 2.22-2.17 (dd, J=17.5, 1.5 Hz, 1H), 2.13-2.10 (m, 1H),
1.90-1.86 (m, 1H), 1.62-1.56 (m, 1H).
b)
4-(Benzyloxy)-1-(10,11-dimethyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohe-
pta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00141##
[0378]
2-Bromo-10,11-dimethyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4-
,5]pyrrolo[2,3-b]pyridine (33.0 mg, 100 .mu.mol) and
4-(benzyloxy)pyridin-2(1H)-one (26.0 mg, 0.130 mmol), CuI (28.5 mg,
0.150 mmol), 8-hydroxyquinoline (2.90 mg, 20.0 .mu.mol) and
Cs.sub.2CO.sub.3 (65.0 mg, 20.0 .mu.mol) in DMSO (2 mL) were
reacted following the procedure for Example 2 (steps c and d) to
provide the free base of the title compound (8.00 mg) as a yellow
solid. 1.25 M HCl in methanol (0.5 mL, 0.6 mmol) was added to a
solution of the solid in MeOH (1 mL). Concentration under vacuum
provided the title compound (7.70 mg, 17%) as a yellow solid. Free
Base: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.85 (d, J=8.0 Hz,
1H), 7.67 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.43-7.35 (m,
5H), 6.13-6.10 (dd, J=8.0, 2.5 Hz, 1H), 6.06 (d, J=2.0
[0379] Hz, 1H), 5.07 (s, 2H), 4.70-4.50 (m, 1H), 4.10-4.00 (m, 1H),
3.73 (s, 3H), 3.50-3.30 (m, 1H), 2.72-2.57 (m, 6H), 2.10-2.06 (m,
1H), 1.77-1.73 (m, 1H); HPLC (Method C) 96.6% (AUC), t.sub.R=14.3
min. HCl salt: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.07 (d,
J=8.0 Hz, 1H), 7.79 (dd, J=8.0, 3.5 Hz, 1H), 7.47 (d, J=7.0 Hz,
2H), 7.40-7.39 (m, 2H), 7.34-7.36 (m, 2H), 6.32 (dd, J=7.5, 2.5 Hz,
1H), 6.11 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 5.18-5.10 (m, 1H),
4.39-4.35 (m, 1H), 3.79 (s, 1H), 3.76 (s, 2H), 3.63-3.50 (m, 1H),
3.18-3.15 (m, 1H), 2.99 (s, 2H), 2.86 (s, 1H), 2.66-2.50 (m, 2H),
2.35-2.29 (m, 1H), 2.11-2.06 (m, 1H); ESI MS m/z 427 [M+H].sup.+;
HPLC (Method A) 95.8% (AUC), t.sub.R=12.9 min.
Example 43
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-
-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a) tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate
##STR00142##
[0381] To a solution of
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine (283 mg, 0.970 mol) in methylene chloride (10 mL)
was added Boc.sub.2O (209 mg, 0.970 mmol), DMAP (59.0 mg, 0.40
mmol) and triethylamine (400 .mu.L, 2.90 mmol), and the reaction
progressed at room temperature for 18 h. The mixture was washed
with water (10 mL) and saturated aqueous sodium bicarbonate
(2.times.10 mL). The organic phase was removed, dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness. The
resulting mixture was purified by flash column chromatography
(silica gel, hexanes/EtOAc, 100:0 to 0:100) to give the title
compound (163 mg, 43%) as a yellow oil: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.62 (d, J=8.0 Hz, 1H), 7.16 (d, J=6.5 Hz, 1H),
5.30-5.00 (m, 1H), 4.80-4.60 (m, 1H), 3.67 (s, 3H), 3.52-3.30 (m,
1H), 2.51-2.47 (d, J=16.0 Hz, 1H), 2.20-2.14 (m, 1H), 2.10-2.00 (m,
1H), 1.93-1.89 (m, 1H), 1.67-1.65 (m, 1H), 1.43-1.34 (m, 9H).
b)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5-
,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00143##
[0383] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (80 mg, 200 .mu.mol),
4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (53 mg, 240
.mu.mol), CuI (46 mg, 240 .mu.mol), 8-hydroxyquinoline (5.8 mg, 40
.mu.mol) and Cs.sub.2CO.sub.3 (130 mg, 400 .mu.mol) in DMSO (2 mL)
were reacted following the procedure for Example 2 (step c) to
provide tert-butyl
2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6-
,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carb-
oxylate (37 mg) as a yellow solid.
[0384] tert-Butyl
2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6-
,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carb-
oxylate (37.0 mg, 69.8 .mu.mol) was deprotected and converted to
the hydrochloride salt according to the procedure for Example 2
(step d) to provide the title compound (31.0 mg, 33%) as an
off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.54 (d,
J=2.5 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H),
7.77-7.73 (m, 1H), 7.71-7.67 (m, 1H), 7.36 (d, J=8.5 Hz, 1H), 6.37
(dd, J=7.5, 2.5 Hz, 1H), 6.13 (d, J=2.5 Hz, 1H), 5.29 (s, 2H), 5.25
(d, J=5.0 Hz, 1H), 4.58-4.55 (m, 1H), 3.76 (s, 3H), 3.56-3.51 (dd,
J=18.0, 5.0 Hz, 1H), 3.15-3.10 (dd, J=17.5, 1.0 Hz, 1H), 2.51-2.29
(m, 3H), 2.05-2.01 (m, 1H); ESI MS m/z 432 [M+H].sup.+; HPLC
(Method A) 98.0% (AUC), t.sub.R=11.4 min.
Example 44
Preparation of
1-(10-Methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b-
]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
hydrochloride
a) tert-Butyl
10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5-
,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-ca-
rboxylate
##STR00144##
[0386] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (278 mg, 0.700 mmol),
4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (169 mg, 0.700
mmol), CuI (202 mg, 1.10 mmol), 8-hydroxyquinoline (20.0 mg, 0.140
mmol) and Cs.sub.2CO.sub.3 (462 mg, 1.40 mmol) in DMSO (10 mL) were
reacted following the procedure for Example 2 (step c) to provide
the title compound (60.4 mg, 15%) as a yellow solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.99 (d, J=1.5 Hz, 1H), 8.10 (dd,
J=8.5, 2.0 Hz, 1H), 7.99-7.91 (m, 2H), 7.82 (d, J=8.0 Hz, 1H),
7.53-7.46 (m, 1H), 6.92 (d, J=1.5 Hz, 1H), 6.54 (d, J=7.0 Hz, 1H),
5.40-5.10 (m, 1H), 4.80-4.60 (m, 1H), 3.70 (s, 3H), 3.60-3.30 (m,
1H), 2.57-2.53 (d, J=16.5 Hz, 1H), 2.35-2.33 (m, 1H), 2.26-2.18 (m,
1H), 1.97-1.93 (m, 1H), 1.70-1.60 (m, 1H), 1.50-1.30 (m, 9H).
b)
1-(10-Methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-
-b]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
hydrochloride
##STR00145##
[0388] tert-Butyl
10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5-
,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-ca-
rboxylate (60.0 mg, 0.100 mmol) was deprotected and converted to
the hydrochloride salt according to the procedure for Example 2
(step d) to provide the title compound (27.0 mg, 56%) as a yellow
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.11 (s, 1H), 8.42
(d, J=8.0 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.06 (d, J=7.0 Hz, 1H),
7.98 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.03 (d, J=1.5 Hz,
1H), 6.92 (dd, J=7.5, 2.0 Hz, 1H), 5.28 (d, J=5.0 Hz, 1H), 4.59 (m,
1H), 3.79 (s, 3H), 3.58-3.53 (dd, J=17.5, 5.0 Hz, 1H), 3.17-3.13
(d, J=17.5 Hz, 1H), 2.52-2.31 (m, 3H), 2.06-2.03 (m, 1H); ESI MS
m/z 452 [M+H].sup.+; HPLC (Method A) 96.3% (AUC), t.sub.R=12.6
min.
Example 45
Preparation of
4-(2,4-Difluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocy-
clohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a) 4-(2,4-Difluorobenzyloxy)pyridin-2(1H)-one
[0389] (CAS Registry Number 586373-58-2) (WO 2003/068230 to Devadas
et al., which is hereby incorporated by reference in its
entirety)
##STR00146##
[0390] A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7
mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol),
Cs.sub.2CO.sub.3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and
1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was
degassed by bubbling N.sub.2 through the suspension for 15 min. The
suspension was put under N.sub.2, and heated at 105.degree. C. for
18 h. The suspension was cooled, EtOAc (50 mL) was added, and the
resulting suspension was passed through a plug of SiO.sub.2. The
resulting solution was concentrated under reduced pressure. Flash
chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to
0:100) afforded a white solid. A suspension of the white solid and
NH.sub.4OAc (8.21 g, 107 mmol) in 1:1 HCO.sub.2H/H.sub.2O (40 mL)
was heated at reflux with stirring for 4 d. The solution was cooled
and concentrated under reduced pressure. The resulting residue was
made basic with saturated NaHCO.sub.3 solution, and the resulting
suspension was filtered. The solid was washed with H.sub.2O and
dried under reduced pressure to afford 3.16 g (44%) of the title
compound as a white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33
(ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd,
J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).
b) tert-Butyl
2-(4-(2,4-difluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6,7,8,9,1-
0-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate
##STR00147##
[0392] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (130 mg, 0.330 mmol),
4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (78.0 mg, 0.330 mmol),
CuI (94.0 mg, 0.500 mmol), 8-hydroxyquinoline (9.50 mg, 0.060 mmol)
and Cs.sub.2CO.sub.3 (215 mg, 0.660 mmol) in DMSO (8 mL) were
reacted following the procedure for Example 2 (step c) to provide
the title compound (46.5 mg, 26%) as an off-white solid: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 7.87 (d, J=8.0 Hz, 1H), 7.80-7.60
(m, 1H), 7.47-7.42 (m, 2H), 6.95-6.86 (m, 2H), 6.07-6.05 (m, 2H),
5.30-5.10 (m, 1H), 5.07 (s, 2H), 4.80-4.60 (m, 1H), 3.67 (s, 3H),
3.55-3.36 (m, 1H), 2.54-2.51 (d, J=16.0 Hz, 1H), 2.40-2.30 (m, 1H),
2.24-2.16 (m, 1H), 1.95-1.91 (m, 1H), 1.70-1.60 (m, 1H), 1.50-1.30
(m, 9H).
c)
4-(2,4-Difluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-imino-
cyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00148##
[0394] tert-Butyl
2-(4-(2,4-difluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6,7,8,9,1-
0-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate
(46 mg, 0.080 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (35.0 mg, 90%) as an off-white
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.10 (d, J=8.5 Hz,
1H), 7.79 (d, J=7.5 Hz, 1H), 7.59 (m, 1H), 7.38 (d, J=8.5 Hz, 1H),
7.07-7.02 (m, 2H), 6.29 (dd, J=7.5, 2.5 Hz, 1H), 6.15 (d, J=2.5 Hz,
1H), 5.40-5.25 (m, 1H), 5.20 (s, 2H), 4.70-4.50 (m, 1H), 3.76 (s,
3H), 3.55-3.51 (dd, J=17.5, 4.5 Hz, 1H), 3.15-3.11 (d, J=18.0 Hz,
1H), 2.51-2.29 (m, 3H), 2.05-1.99 (m, 1H); ESI MS m/z 449
[M+H].sup.+; HPLC (Method A) 97.6% (AUC), t.sub.R=13.2 min.
Example 46
Preparation of
4-(4-Chlorophenethyl)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocycloh-
epta[4,5]pyrrolo[2,3-b]pyridin-2-yl)-piperazin-2-one
dihydrochloride
a) 4-(4-Chlorophenethyl)piperazin-2-one
##STR00149##
[0396] Piperazinone (1.04 g, 10.4 mmol),
1-chloro-4-(2-chloroethyl)benzene (2.28 g, 10.4 mmol) and
K.sub.2CO.sub.3 (1.72 g, 12.4 mmol) were combined in DMSO (12 mL)
and heated to 85.degree. C. for 2 h. The mixture was partitioned
between H.sub.2O (20 mL) and CH.sub.2Cl.sub.2 (20 mL), and the
organic layer was removed. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL), the combined organics were
concentrated, and the residue was dissolved in 2 N HCl (50 mL).
This acidic mixture was washed with CH.sub.2Cl.sub.2 (3.times.20
mL) and then made basic with 6 N NaOH. The basic mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.20 mL), and the extracts
were combined, dried and concentrated to provide the title compound
(1.51 g, 60%) as an orange solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.72 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.26
(d, J=8.8 Hz, 2H), 3.14-3.10 (m, 2H), 2.96 (s, 2H), 2.74 (t, J=6.6
Hz, 2H), 2.62-2.53 (m, 4H).
b)
4-(4-Chlorophenethyl)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocycl-
ohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)-piperazin-2-one
dihydrochloride
##STR00150##
[0398] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (214 mg, 0.550 mmol),
4-(4-chlorophenethyl)piperazin-2-one (131 mg, 0.550 mmol), CuI (157
mg, 0.530 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (17.0
.mu.L, 0.110 mmol) and Cs.sub.2CO.sub.3 (358 mg, 1.10 mmol) in
dioxane (5 mL) were reacted following the procedure for Example 2
(step c) to give tert-butyl
2-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-10-methyl-5,6,7,8,9,10-hexa-
hydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate
(83.3 mg) as a yellow oil.
[0399] tert-Butyl
2-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-10-methyl-5,6,7,8,9,10-hexa-
hydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate
(83.3 mg, 0.150 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (30 mg, 11%) as an off-white
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.03 (d, J=8.5 Hz,
1H), 7.57 (d, J=8.0 Hz, 1H), 7.40-7.34 (m, 4H), 5.22 (d, J=5.5 Hz,
1H), 4.57-4.54 (m, 1H), 4.40-4.20 (m, 4H), 4.00-3.80 (m, 2H), 3.74
(s, 3H), 3.60 (t, J=8.5 Hz, 2H), 3.54-3.50 (dd, J=17.5, 4.5 Hz,
1H), 3.20-3.16 (m, 2H), 3.12-3.08 (d, J=17.5 Hz, 1H), 2.50-2.26 (m,
3H), 2.03-2.00 (m, 1H); ESI MS m/z 450 [M+H].sup.+; HPLC (Method A)
98.7% (AUC), t.sub.R=11.0 min.
Example 47
Preparation of
4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-im-
inocyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a) 4-(4-Chloro-2-fluorobenzyloxy)pyridin-2(1H)-one
##STR00151##
[0401] A suspension of (4-chloro-2-fluorophenyl)methanol (3.24 g,
20.1 mmol), 2-chloro-4-iodopyridine (4.40 g, 18.3 mmol),
Cs.sub.2CO.sub.3 (7.76 g, 23.8 mmol), CuI (3.48 g, 18.7 mmol) and
1,10-phenanthroline (659 mg, 3.66 mmol) in toluene (20 mL) was
degassed by bubbling N.sub.2 through the suspension for 15 min. The
suspension was put under N.sub.2 and heated at 105.degree. C. for
18 h. The suspension was cooled, 9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (10 mL) was added, and the
resulting suspension was passed through a plug of SiO.sub.2. The
resulting solution was concentrated under reduced pressure. Flash
chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to
0:100) afforded a white solid. A suspension of the white solid and
NH.sub.4OAc (2.66 g, 34.6 mmol) in 1:1 HCO.sub.2H/H.sub.2O (20 mL)
was heated at reflux with stirring for 4 d. The solution was cooled
and concentrated under reduced pressure. The resulting residue was
made basic with saturated NaHCO.sub.3 solution, and the resulting
suspension was filtered. The solid was washed with H.sub.2O and
CH.sub.2Cl.sub.2, and dried under reduced pressure to afford 1.28 g
(28%) of the title compound as a white solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz,
1H), 7.52 (dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H),
7.25 (d, J=7.2 Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4
Hz, 1H), 5.06 (s, 2H).
b) tert-Butyl
2-(4-(4-chloro-2-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6,7,-
8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxy-
late
##STR00152##
[0403] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (220 mg, 0.560 mmol),
4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (142 mg, 0.560
mmol), CuI (160 mg, 0.84 mmol), 8-hydroxyquinoline (16 mg, 0.11
mmol) and Cs.sub.2CO.sub.3 (365 mg, 1.10 mmol) in DMSO (8 mL) were
reacted following the procedure for Example 2 (step c) to provide
the title compound (85.0 mg, 27%) as a yellow solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.88 (d, J=8.5 Hz, 1H), 7.80-7.60 (m,
1H), 7.43-7.39 (m, 2H), 7.21-7.14 (m, 2H), 6.08-6.05 (m, 2H),
5.30-5.10 (m, 1H), 5.08 (s, 2H), 4.80-4.60 (m, 1H), 3.67 (s, 3H),
3.55-3.36 (m, 1H), 2.54-2.51 (d, J=16.5 Hz, 1H), 2.40-2.30 (m, 1H),
2.30-2.10 (m, 1H), 1.95-1.91 (m, 1H), 1.70-1.60 (m, 1H), 1.50-1.30
(m, 9H).
c)
4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8--
iminocyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00153##
[0405] tert-Butyl
2-(4-(4-chloro-2-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6,7,-
8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxy-
late (85.0 mg, 0.150 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (48.0 mg, 64%) as an off-white
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.10 (d, J=8.5 Hz,
1H), 7.79 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.38 (d, J=8.0 Hz,
1H), 7.32-7.28 (m, 2H), 6.30 (dd, J=8.0, 3.0 Hz, 1H), 6.14 (d,
J=2.5 Hz, 1H), 5.26 (d, J=5.5 Hz, 1H), 5.22 (s, 2H), 4.58-4.55 (m,
1H), 3.76 (s, 3H), 3.55-3.51 (dd, J=17.5, 4.5 Hz, 1H), 3.15-3.11
(d, J=17.5 Hz, 1H), 2.51-2.29 (m, 3H), 2.05-2.01 (m, 1H); ESI MS
m/z 465 [M+H].sup.+; HPLC (Method A) 97.7% (AUC), t.sub.R=13.9
min.
Example 48
Preparation of
4-(2,4-Dichlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocy-
clohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a) 4-(2,4-Dichlorobenzyloxy)pyridin-2(1H)-one
[0406] (CAS Registry Number 1182243-20-4) (WO 2007/043835 to Kim et
al., which is hereby incorporated by reference in its entirety)
##STR00154##
[0407] A suspension of (2,4-dichlorophenyl)methanol (4.10 g, 23.2
mmol), 2-chloro-4-iodopyridine (5.05 g, 21.1 mmol),
Cs.sub.2CO.sub.3 (8.94 g, 27.4 mmol), CuI (4.01 g, 21.1 mmol) and
1,10-phenanthroline (760 mg, 4.22 mmol) in toluene (20 mL) was
degassed by bubbling N.sub.2 through the suspension for 15 min. The
suspension was put under N.sub.2, and heated at 105.degree. C. for
18 h. The suspension was cooled, EtOAc (50 mL) was added, and the
resulting suspension was passed through a plug of SiO.sub.2. The
resulting solution was concentrated under reduced pressure. Flash
chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to
0:100) afforded a white solid. A suspension of the white solid and
NH.sub.4OAc (6.13 g, 79.5 mmol) in 1:1 HCO.sub.2H/H.sub.2O (40 mL)
was heated at reflux with stirring for 4 d. The solution was cooled
and concentrated under reduced pressure. The resulting residue was
made basic with saturated NaHCO.sub.3 solution and the resulting
suspension was filtered. The solid was washed with H.sub.2O and
dried under reduced pressure. Flash chromatography on silica gel
((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH),
100:0 to 0:100) afforded 1.36 g (24%) of the title compound as a
white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.16 (br
s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.1, 1H), 7.50 (dd,
J=8.4, 2.1 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.91 (dd, J=7.5, 2.7
Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.10 (s, 2H).
b) tert-Butyl
2-(4-(2,4-dichlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6,7,8,9,1-
0-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate
##STR00155##
[0409] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (232 mg, 0.590 mmol),
4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (159 mg, 0.590 mmol),
CuI (168 mg, 0.880 mmol), 8-hydroxyquinoline (17.0 mg, 0.120 mmol)
and Cs.sub.2CO.sub.3 (384 mg, 1.20 mmol) in DMSO (8 mL) were
reacted following the procedure for Example 2 (step c) to provide
the title compound (114 mg, 33%) as a yellow solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.19 (d, J=8.5 Hz, 1H), 7.80-7.60 (m,
1H), 7.50-7.40 (m, 3H), 7.30 (d, J=7.0 Hz, 1H), 6.11 (d, J=7.5 Hz,
1H), 6.05 (s, 1H), 5.30-5.10 (m, 1H), 5.02 (s, 2H), 4.80-4.60 (m,
1H), 3.67 (s, 3H), 3.55-3.36 (m, 1H), 2.54-2.51 (d, J=16.5 Hz, 1H),
2.40-2.30 (m, 1H), 2.30-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.70-1.60
(m, 1H), 1.50-1.30 (m, 9H).
c)
4-(2,4-Dichlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydro-5,8-imino-
cyclohepta[4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00156##
[0411] tert-Butyl
2-(4-(2,4-dichlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,6,7,8,9,1-
0-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxylate
(114 mg, 0.190 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (44.0 mg, 45%) as an off-white
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.10 (d, J=8.0 Hz,
1H), 7.80 (d, J=7.5 Hz, 1H), 7.59-7.57 (m, 2H), 7.42 (dd, J=8.5,
2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 6.32 (dd, J=8.0, 2.5 Hz, 1H),
6.12 (d, J=2.5 Hz, 1H), 5.25 (m, 3H), 4.58-4.56 (m, 1H), 3.76 (s,
3H), 3.55-3.51 (dd, J=18.0, 4.5 Hz, 1H), 3.15-3.11 (d, J=17.5 Hz,
1H), 2.51-2.29 (m, 3H), 2.05-1.99 (m, 1H); ESI MS m/z 481
[M+H].sup.+; HPLC (Method A) 99.1% (AUC), t.sub.R=14.4 min.
Example 49
Preparation of
1-(10-Methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b-
]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
a) tert-Butyl
10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-
,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-ca-
rboxylate
##STR00157##
[0413] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (250 mg, 0.630 mmol),
4-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (152 mg, 0.630
mmol), CuI (180 mg, 0.940 mmol), 8-hydroxyquinoline (18.0 mg, 0.120
mmol) and Cs.sub.2CO.sub.3 (410 mg, 1.20 mmol) in DMSO (10 mL) were
reacted following the procedure for Example 2 (step c) to provide
the title compound (25.5 mg, 7%) as a yellow solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 9.00 (d, J=2.0 Hz, 1H), 8.06 (dd,
J=8.5, 2.5 Hz, 1H), 7.99-7.91 (m, 3H), 7.60-7.40 (m, 2H), 7.08 (d,
J=7.5 Hz, 1H), 5.40-5.10 (m, 1H), 4.80-4.60 (m, 1H), 3.70 (s, 3H),
3.60-3.40 (m, 1H), 2.57-2.53 (d, J=16.5 Hz, 1H), 2.40-2.30 (m, 1H),
2.30-2.20 (m, 1H), 2.00-1.90 (m, 1H), 1.70-1.60 (m, 1H), 1.50-1.30
(m, 9H).
b)
1-(10-Methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-
-b]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
hydrochloride
##STR00158##
[0415] tert-Butyl
10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-
,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-ca-
rboxylate (25.0 mg, 40.0 .mu.mol) was deprotected and converted to
the hydrochloride salt according to the procedure for Example 2
(step d) to provide the title compound (5.8 mg, 30%) as a yellow
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.06 (s, 1H),
8.30-8.27 (m, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H),
8.05 (d, J=7.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.5 Hz,
1H), 7.28 (dd, J=7.0, 1.5 Hz, 1H), 5.28 (d, J=5.5 Hz, 1H),
4.59-4.56 (m, 1H), 3.79 (s, 3H), 3.57-3.52 (dd, J=17.5, 4.5 Hz,
1H), 3.17-3.13 (d, J=17.5 Hz, 1H), 2.52-2.31 (m, 3H), 2.06-2.03 (m,
1H); ESI MS m/z 452 [M+H].sup.+; HPLC (Method A) 90.2% (AUC),
t.sub.R=13.0 min.
Example 50
Preparation of
1-(10-Methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b-
]pyridin-2-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one
hydrochloride
a) 4-(4-(Trifluoromethyl)phenyl)pyridine 1-oxide
[0416] (CAS Registry Number 545396-52-9) (WO 2003/049702 to Bo et
al., which is hereby incorporated by reference in its entirety)
##STR00159##
[0417] 4-Chloropyridine-N-oxide (3.0 g, 23 mmol),
4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol),
K.sub.2CO.sub.3 (4.8 g, 35 mmol) and PdCl.sub.2(dppf) (470 mg, 0.57
mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The
flask was flushed with nitrogen, and the mixture was heated to
80.degree. C. for 10 min. Upon cooling, the mixture was diluted
with methylene chloride and washed with 5% lithium chloride
solution (5.times.), dried, concentrated, and the residue was
purified by flash column chromatography (40 g ISCO column eluting
with methylene chloride and a methanol/ammonia mixture (10:1);
gradient 100% methylene chloride to 80% methylene chloride over 30
min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a
tan solid: ESI MS m/z 240 [M+H].sup.+.
b) 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one
[0418] (CAS Registry Number 942947-10-6) (U.S. Published Patent
Application No. 2007/149513 to Chen et al., which is hereby
incorporated by reference in its entirety)
##STR00160##
[0419] 4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9
mmol) was heated to 140.degree. C. in acetic anhydride (80 mL) for
5 h. The mixture was concentrated and then heated at 80.degree. C.
for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL).
The resulting black solution was concentrated to a volume of 15 mL,
and the solid was filtered off, rinsed with CH.sub.2Cl.sub.2 and
dried under vacuum to provide the title compound (1.26 g, 66%) as a
brown solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.80-7.74
(br m, 5H), 6.85-6.66 (br m, 2H).
c)
1-(10-Methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-
-b]pyridin-2-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one
hydrochloride
##STR00161##
[0421] tert-Butyl
2-bromo-10-methyl-5,6,7,8,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[-
2,3-b]pyridine-11-carboxylate (470 mg, 1.20 mmol),
4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (228 mg, 0.960
mmol), CuI (342 mg, 1.80 mmol), 8-hydroxyquinoline (34.0 mg, 0.240
mmol) and Cs.sub.2CO.sub.3 (782 mg, 2.40 mmol) in DMSO (15 mL) were
reacted following the procedure for Example 2 (step c) to provide
tert-butyl
10-methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-5,6,7,8-
,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxyl-
ate (82.0 mg) as a brown oil.
[0422] tert-butyl
10-methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-5,6,7,8-
,9,10-hexahydro-5,8-iminocyclohepta[4,5]pyrrolo[2,3-b]pyridine-11-carboxyl-
ate (82.0 mg, 0.150 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure for Example 2 (step
d) to provide the title compound (25 mg, 4%) as a yellow solid:
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.15 (d, J=8.0 Hz, 1H),
8.01 (d, J=7.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz,
2H), 7.48 (d, J=8.0 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 6.89 (dd,
J=7.5, 2.0 Hz, 1H), 5.28 (d, J=5.0 Hz, 1H), 4.59-4.56 (m, 1H), 3.79
(s, 3H), 3.57-3.52 (dd, J=17.5, 4.5 Hz, 1H), 3.17-3.13 (d, J=17.5
Hz, 1H), 2.52-2.31 (m, 3H), 2.07-2.00 (m, 1H); ESI MS m/z 451
[M+H].sup.+; HPLC (Method A) 95.8% (AUC), t.sub.R=14.0 min.
Example 51
Binding Assay for Human Melanin-Concentrating Hormone (MCH-1)
Receptor
[0423] Evaluation of the affinity of compounds for the human MCH-1
receptor was accomplished using
4-(3,4,5-tritritiumbenzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol--
5-yl)pyridin-2(1H)-one and membranes prepared from stable CHO-K1
cells expressing the human MCH1 receptor obtained from Euroscreen
(Batch 1138). Cell membrane homogenates (8.92 .mu.g protein) were
incubated for 60 min at 25.degree. C. with 1.4 .mu.M of the
[.sup.3H]-labeled compound in the absence or presence of the test
compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding was
determined in the presence of 50 .mu.M
1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromet-
hyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea. Following
incubation, the samples were filtered rapidly under vacuum through
Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, and
washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting
9,9,0) using a Skatron cell harvester. The filters were counted for
radioactivity in a liquid scintillation counter (Tri-Carb 2100TR,
Packard) using a scintillation cocktail (Ultima Gold MV, Perkin
Elmer).
[0424] The results are expressed as a percent inhibition of the
control radioligand specific binding. The IC.sub.50 value
(concentration causing a half-maximal inhibition of control
specific binding) and Hill coefficient (n.sub.H) were determined by
non-linear regression analysis of the competition curve using Hill
equation curve fitting. The inhibition constant (K.sub.i) was
calculated from the Cheng Prusoff equation:
(K.sub.i=IC.sub.50/(1+(L/K.sub.D)), where L=concentration of
radioligand in the assay, and K.sub.D=affinity of the radioligand
for the receptor.
[0425] By methods as described above, the compounds listed in Table
1 were synthesized and tested for biological activity.
TABLE-US-00005 TABLE 1 Compounds Tested for Biological Activity Ex.
MCH-1 Mass No. Structure Ki (nM) Spec .sup.1H NMR Data 2
##STR00162## 10.5 412 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.64 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.49-7.30 (m,
6H), 7.07-7.04 (dd, J = 8.3, 1.7 Hz, 1H), 6.33-6.30 (dd, J = 7.6,
2.6 Hz, 1H), 6.14 (d, J = 2.6 Hz, 1H), 5.23 (d, J = 4.6 Hz, 1H),
5.19 (s, 2H), 4.59-4.48 (m, 1H), 3.69 (s, 3H), 3.55-3.46 (dd, J =
17.3, 4.4 Hz, 1H), 3.05 (d, J = 17.3 Hz, 1H), 2.53-2.23 (m, 3H),
2.04- 1.90 (m, 1H) 3 ##STR00163## 24.4 452 .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.53 (d, J = 8.9 Hz, 1H), 8.27 (d, J = 8.9 Hz,
1H), 7.90 (d, J = 7.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.58 (d, J
= 1.3 Hz, 1H), 7.43 (d, J = 1.3 Hz, 1H), 7.35-7.32 (dd, J = 7.1,
2.0 Hz, 1H), 7.19-7.15 (dd, J = 8.4, 1.8 Hz, 1H), 5.26 (d, J = 4.6
Hz, 1H), 4.57-4.54 (m, 1H), 3.78 (s, 3H), 3.55-3.48 (dd, J = 17.0,
4.6 Hz, 1H), 3.09 (d, J = 17.5 Hz, 1H), 2.53-2.24 (m, 3H),
2.06-1.95 (m, 1H) 4 ##STR00164## 16.1 451 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.05 (s, 1H), 8.29-8.27 (dd, J = 8.4, 2.0 Hz,
1H), 8.23 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.70 (d, J
= 8.3 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H),
7.25-7.24 (dd, J = 7.1, 2.0 Hz, 1H), 7.17- 7.14 (dd, J = 8.3, 1.8
Hz, 1H), 5.26 (d, J = 5.2 Hz, 1H), 4.58-4.53 (m, 1H), 3.72 (s, 3H),
3.53-3.49 (dd, J = 17.2, 4.5 Hz, 1H), 3.09 (d, J = 17.2 Hz, 1H),
2.53-2.35 (m, 2H), 2.32-2.27 (dd, J = 11.7, 9.7 Hz, 1H), 2.03-1.96
(m, 1H) 5 ##STR00165## 6.5 451 .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 9.10 (s, 1H), 8.43-8.39 (dd, J = 8.9, 1.9 Hz, 1H), 7.97 (d,
J = 8.2 Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.70 (d, J = 8.4 Hz,
1H), 7.55 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1H), 7.02
(d, J = 1.6 Hz, 1H), 6.90-6.87 (dd, J = 7.1, 2.0 Hz, 1H), 5.27 (d,
J = 4.7 Hz, 1H), 4.59-4.53 (m, 1H), 3.72 (s, 3H), 3.53-3.48 (dd, J
= 17.5, 4.5 Hz, 1H), 3.08 (d, J = 17.1 Hz, 1H), 2.52-2.26 (m, 3H),
2.04-2.00 (m, 1H) 6 ##STR00166## 13.5 431 .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.54 (d, J = 2.7 Hz, 1H), 7.79-7.63 (m, 4H),
7.46 (d, J = 1.6 Hz, 1H), 7.08-7.04 (dd, J = 8.4, 1.8 Hz, 1H),
6.40-6.37 (dd, J = 7.6, 2.7 Hz, 1H), 6.18 (d, J = 2.6 Hz, 1H), 5.29
(s, 2H), 5.24 (d, J = 4.7 Hz, 1H), 4.58-4.50 (m, 1H), 3.70 (s, 3H),
3.54-3.46 (dd, J = 17.2, 4.9 Hz, 1H), 3.07 (d, J = 17.1 Hz, 1H),
2.51-2.23 (m, 3H), 2.02-1.99 (m, 1H) 7 ##STR00167## 68.1 452
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 9.36 (s, 2H), 7.87 (d, J
= 7.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H),
7.16- 7.13 (dd, J = 8.4, 1.8 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H),
6.93-6.93 (dd, J = 7.1, 2.0 Hz, 1H), 5.26 (d, J = 4.7 Hz, 1H),
4.58-4.52 (m, 1H), 3.79 (s, 3H), 3.56-3.47 (dd, J = 17.3, 4.4 Hz,
1H), 3.12 (dd, J = 17.3, 1.4 Hz, 1H), 2.53-2.23 (m, 3H), 2.04-1.98
(m, 1H) 8 ##STR00168## 9.8 398 .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.39 (s, 1H), 9.54 (br s, 1H), 9.14 (d, J = 9.8 Hz, 1H),
7.60 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.48-7.44 (m,
2H), 7.44-7.40 (m, 2H), 7.37 (dd, J = 8.0, 8.0 Hz, 1H), 7.29 (d, J
= 1.8 Hz, 1H), 6.95-6.93 (dd, J = 8.3, 1.8 Hz, 1H), 6.09-6.07 (dd,
J = 7.6, 2.6 Hz, 1H), 5.96 (d, J = 2.7 Hz, 1H), 5.18 (br s, 1H),
5.14 (s, 2H), 4.40 (br m, 1H), 3.44-3.40 (dd, J = 17.0, 4.0 Hz,
1H), 2.90 (d, J = 17.0 Hz, 1H), 2.29- 2.26 (m, 2H), 2.07-2.04 (m,
1H), 1.80-1.75 (m, 1H) 9 ##STR00169## 25.3 417 .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.42 (s, 1H), 9.63 (d, J = 6.9 Hz, 1H),
9.18 (d, J = 9.7 Hz, 1H), 8.62 (d, J = 2.9 Hz, 1H), 7.97- 7.86 (d,
J = 8.4 Hz, 1H), 7.68-7.63 (dd, J = 8.6, 4.6 Hz, 1H), 7.62 (d, J =
8.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H),
6.94-6.92 (dd, J = 8.4, 1.9 Hz, 1H), 6.14-6.10 (dd, J = 7.6, 2.7
Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.21 (s, 2H), 5.18 (br m, 1H),
4.39 (br m, 1H), 3.46-3.39 (dd, J = 17.1, 4.5 Hz, 1H), 2.87 (d, J =
16.9 Hz, 1H), 2.34-2.22 (m, 2H), 2.11-2.00 (m, 1H), 1.84- 1.74 (m,
1H) 10 ##STR00170## 22.7 437 .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.48 (s, 1H), 9.58-9.47 (br m, 1H), 9.20-9.15 (m, 2H),
8.51-8.47 (dd, J = 8.4, 1.8 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.84
(d, J = 7.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 1.8 Hz,
1H), 7.07-7.04 (dd, J = 8.4, 1.8 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H),
6.80-6.77 (dd, J = 7.2, 2.0 Hz, 1H), 5.21 (br m, 1H), 4.42 (br m,
1H), 3.47-3.40 (dd, J = 17.3, 4.4 Hz, 1H), 2.90 (d, J = 16.9 Hz,
1H), 2.30-2.23 (m, 2H), 2.07 (t, J = 9.8 Hz, 1H), 1.85-1.75 (m, 1H)
11 ##STR00171## 21.3 445 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
8.60 (s, 1H), 7.88-7.80 (ddd, J = 8.2, 2.8, 2.8 Hz, 1H), 7.80-7.70
(m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H),
7.09-7.05 (dd, J = 8.4, 1.8 Hz, 1H), 6.52-6.48 (dd, J = 7.6, 2.8
Hz, 1H), 6.26 (d, J = 2.6 Hz, 1H), 5.35 (s, 2H), 5.09 (br m 1H),
4.18-4.15 (m, 1H), 3.76 (s, 3H), 3.54-3.42 (dd, J = 18.0, 7.3 Hz,
1H), 3.13 (d, J = 18.0 Hz, 1H), 2.23-1.84 (m, 4H), 1.61-1.40 (m,
2H) 12 ##STR00172## 9.3 426 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.77 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.53
(d, J = 1.7 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.42 (dd, J = 2.9,
2.9 Hz, 2H), 7.39-7.35 (m, 1H), 7.09-7.07 (dd, J = 8.3, 1.8 Hz,
1H), 6.54-6.52 (dd, J = 7.5, 2.8 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H),
5.26 (s, 2H), 5.09 (br m 1H), 4.17-4.15 (m, 1H), 3.76 (s, 3H),
3.53-3.49 (dd, J = 17.9, 7.5 Hz, 1H), 3.12 (d, J = 17.9 Hz, 1H),
2.20-2.07 (m, 2H), 2.02-1.89 (m, 2H), 1.62-1.56 (m, 1H), 1.50-1.39
(m, 1H) 13 ##STR00173## 46.3 465 .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.65 (d, J = 11.4 Hz, 1H), 9.20 (d, J = 2.0
Hz, 1H), 9.10 (d, J = 10.5 Hz, 1H), 8.51-8.48 (dd, J = 8.0, 1.8 Hz,
1H), 8.05 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.64-7.61
(m, 2H), 7.10-7.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.02 (d, J = 1.8 Hz,
1H), 6.83-6.80 (dd, J = 7.2, 2.0 Hz, 1H), 5.05 (br m 1H), 4.09 (br
m, 1H), 3.72 (s, 3H), 3.44-3.22 (m, 1H), 3.04 (d, J = 17.8 Hz, 1H),
2.21-1.96 (m, 2H), 1.88-1.64 (m, 2H), 1.53-1.38 (m, 1H), 1.35-1.17
(m, 1H) 14 ##STR00174## 15.8 412 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.66 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.48-
7.45 (m, 3H), 7.43-7.40 (m, 2H), 7.38-7.34 (m, 1H), 7.08 (dd, J =
6.5, 2.0 Hz, 1H), 6.36 (dd, J = 5.0, 3.0 Hz, 1H), 6.17 (d, J = 2.5
Hz, 1H), 5.24 (d, J = 5.5 Hz, 1H), 5.20 (s, 2H), 4.55-4.53 (m, 1H),
3.70 (s, 3H), 3.52 (dd, J = 12.5, 4.5 Hz, 1H), 3.09 (dd, J = 16.5,
1.0 Hz, 1H), 2.47-2.37 (m, 2H), 2.30-2.25 (m, 1H), 2.00-1.95 (m,
1H) 15 ##STR00175## 7.8 412 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.66 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.48-
7.45 (m, 3H), 7.43-7.40 (m, 2H), 7.38-7.34 (m, 1H), 7.08 (dd, J =
6.5, 2.0 Hz, 1H), 6.36 (dd, J = 5.0, 3.0 Hz, 1H), 6.17 (d, J = 2.5
Hz, 1H), 5.24 (d, J = 5.5 Hz, 1H), 5.20 (s, 2H), 4.55-4.53 (m, 1H),
3.70 (s, 3H), 3.52 (dd, J = 12.5, 4.5 Hz, 1H), 3.09 (dd, J = 16.5,
1.0 Hz, 1H), 2.47-2.37 (m, 2H), 2.30-2.25 (m, 1H), 2.00-1.95 (m,
1H) 16 ##STR00176## 14 451 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.05 (d, J = 0.5 Hz, 1H), 8.28 (dd, J = 8.5, 2.5 Hz, 1H),
8.23 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.70 (d, J =
8.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H),
7.25 (dd, J = 7.0, 2.0 Hz, 1H), 7.16 (dd, J = 8.5, 2.0 Hz, 1H),
5.26 (d, J = 8.0 Hz, 1H), 4.57-4.54 (m, 1H), 3.73 (s, 3H),
3.54-3.49 (dd, J = 17.5, 5 Hz, 1H), 3.12-3.07 (dd, J = 17.0, 1.0
Hz, 1H), 2.48-2.32 (m, 3H), 2.04-1.97 (m, 1H) 17 ##STR00177## 28
446 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.64 (d, J = 11.0
Hz, 1H), 9.04 (d, J = 11.0 Hz, 1H), 8.63 (d, J = 2.9 Hz, 1H), 8.00
(d, J = 2.8 Hz, 1H), 7.89-7.82 (dt, J = 8.7, 2.7 Hz, 1H), 7.73-
7.68 (dd, J = 8.7, 4.6 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.58 (d,
J = 8.5 Hz, 1H), 7.13-7.09 (dd, J = 8.3, 1.8 Hz, 1H), 6.53 (d, J =
2.8 Hz, 1H), 5.29 (s, 2H), 5.03 (s, 1H), 4.16-4.05 (m, 1H), 3.70
(s, 3H), 3.41-3.33 (dd, J = 18.0, 7.3 Hz, 1H), 3.03 (d, J = 18.0
Hz, 1H), 2.16-2.00 (m, 2H), 1.79 (d, J = 13.1 Hz, 1H), 1.70 (d, J =
12.3 Hz, 1H), 1.48 (d, J = 12.6 Hz, 1H), 1.33-1.24 (m, 1H) 18
##STR00178## 73 442 .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.63 (d, J = 10.8 Hz, 1H), 9.06 (d, J = 10.3 Hz, 1H), 8.76 (d, J =
1.7 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 2.9 Hz, 1H),
7.66 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.57 (d, J =
8.5 Hz, 1H), 7.12-7.09 (dd, J = 8.3, 1.8 Hz, 1H), 6.58 (d, J = 2.8
Hz, 1H), 5.34 (s, 2H), 5.03 (s, 1H), 4.08-4.01 (m, 1H), 3.70 (s,
3H), 3.41-3.33 (dd, J = 18.0, 7.5 Hz, 1H), 3.06 (d, J = 17.8 Hz,
1H), 2.63 (s, 3H), 2.17-2.01 (m, 2H), 1.90-1.61 (m, 2H), 1.59-1.44
(m, 1H), 1.32-1.23 (m, 1H) 19 ##STR00179## 13 495 .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 9.71 (d, J = 11.3 Hz, 1H), 9.12 (d, J =
11.1 Hz, 1H), 8.89 (s, 1H), 8.21-8.18 (dd, J = 8.1, 1.4 Hz, 1H),
8.0 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.3
Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.00-6.96 (dd, J = 8.3, 1.8 Hz,
1H), 6.17-6.13 (dd, J = 7.6, 2.8 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H),
5.38 (s, 2H), 5.02 (s, 1H), 4.12-4.00 (m, 1H), 3.70 (s, 3H),
3.41-3.33 (dd, J = 17.9, 7.3 Hz, 1H), 3.03 (d, J = 17.9 Hz, 1H),
2.18-2.02 (m, 2H), 1.80 (d, J = 13.3 Hz, 1H), 1.70 (d, J = 12.9 Hz,
1H), 1.47-1.23 (m, 2H) 20 ##STR00180## 9.3 398 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.37 (s, 1H), 9.26-8.83 (s, 2H), 7.60
(d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49-7.34 (m, 5H),
7.29 (d, J = 1.6 Hz, 1H), 6.95-6.92 (dd, J = 8.4, 1.9 Hz, 1H),
6.13-6.05 (dd, J = 7.6, 2.8 Hz, 1H), 5.90 (d, J = 2.8 Hz, 1H), 5.14
(s, 3H), 4.44-4.37 (m, 1H), 3.44-3.37 (dd, J = 17.2, 4.4 Hz, 1H),
2.85 (d, J = 16.8 Hz, 1H), 2.25-2.19 (m, 2H), 2.07-1.98 (m, 1H),
1.79- 1.75 (m, 1H) 21 ##STR00181## 39 398 .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.41 (s, 1H), 9.58 (s, 1H), 9.16 (s, 1H),
7.60 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.49- 7.34 (m,
5H), 7.29 (d, J = 1.6 Hz, 1H), 6.95- 6.92 (dd, J = 8.4, 1.9 Hz,
1H), 6.10-6.07 (dd, J = 7.6, 2.8 Hz, 1H), 5.90 (d, J = 2.6 Hz, 1H),
5.18 (s, 1H), 5.14 (s, 2H), 4.48-4.25 (m, 1H), 3.46-3.39 (dd, J =
17.2, 4.4 Hz, 1H), 2.88 (d, J = 16.7 Hz, 1H), 2.38-2.15 (m, 2H),
2.07- 1.98 (m, 1H), 1.85-1.66 (m, 1H) 22 ##STR00182## 25 399
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.40 (s, 1H), 9.48 (s,
1H), 9.13 (d, J = 8.6 Hz, 1H), 8.63-8.60 (m, 1H), 7.93-7.87 (td, J
= 8.4, 1.8 Hz, 1H), 7.62-7.55 (m, 3H), 7.43-7.38 (m, 1H), 7.29 (d,
J = 1.6 Hz, 1H), 6.96-6.93 (dd, J = 8.4, 1.9 Hz, 1H), 6.14-6.11
(dd, J = 7.6, 2.8 Hz, 1H), 5.94 (d, J = 2.8 Hz, 1H), 5.21 (s, 2H),
5.18 (s, 1H), 4.41 (s, 1H), 3.40-3.38 (m, 1H), 2.88 (d, J = 16.8
Hz, 1H), 2.29-2.21 (m, 2H), 2.05-2.02 (m, 1H), 1.85-1.76 (m, 1H) 23
##STR00183## 17 413 .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.56 (d, J = 7.3 Hz, 1H), 9.16 (d, J = 10.1 Hz, 1H), 8.63-8.61 (m,
1H), 7.93-7.87 (td, J = 7.7, 2.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),
7.59-7.54 (m, 2H), 7.48 (d, J = 1.6 Hz, 1H), 7.43-7.38 (m, 1H),
7.01-6.94 (dd, J = 8.3, 1.8 Hz, 1H), 6.16-6.13 (dd, J = 7.6, 2.8
Hz, 1H), 5.96 (d, J = 2.7 Hz, 1H), 5.22-5.20 (m, 3H), 4.53-4.37 (m,
1H), 3.64 (s, 3H), 3.42-3.35 (dd, J = 17.3, 4.6 Hz, 1H), 3.02 (d, J
= 16.8 Hz, 1H), 2.29- 2.21 (m, 2H), 2.11-2.02 (m, 1H), 1.85-1.75
(m, 1H) 24 ##STR00184## 7.4 431 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.50 (s, 1H), 7.72-7.64 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H),
7.59 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.03 (dd, J =
8.5, 2.0 Hz, 1H), 6.32 (dd, J = 7.5, 2.5 Hz, 1H), 6.12 (d, J = 3.0
Hz, 1H), 5.26 (s, 2H), 5.10-5.08 (m, 1H), 4.45-4.42 (m, 1H), 3.68
(s, 3H), 3.44 (dd, J = 17.0, 4.5 Hz, 1H), 2.98 (dd, J = 17.0, 1.0
Hz, 1H), 2.41-2.28 (m, 2H), 2.24-2.19 (m, 1H), 1.94-1.88 (m, 1H) 25
##STR00185## 19 431 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.51
(d, J = 2.5 Hz, 1H), 7.72-7.65 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H),
7.59 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.04 (dd, J =
8.5, 2.0 Hz, 1H), 6.32 (dd, J = 7.5, 2.5 Hz, 1H), 6.12 (d, J = 3.0
Hz, 1H), 5.26 (s, 2H), 5.20-5.19 (m, 1H), 4.53-4.50 (m, 1H), 3.69
(s, 3H), 3.48 (dd, J = 17.0, 4.5 Hz, 1H), 3.05 (dd, J = 17.0, 1.0
Hz, 1H), 2.46-2.33 (m, 2H), 2.28-2.23 (m, 1H), 1.99-1.93 (m, 1H) 26
##STR00186## 9.7 426 .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.0 (s, 0.5H), 10.30 (s, 0.5H), 7.61-7.4 (m, 2H), 7.49- 7.34 (m,
6H), 7.03-6.97 (dt, J = 8.4, 1.8 Hz, 1H), 6.12-6.09 (dd, J = 7.6,
2.7 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.15 (s, 2H), 5.11-5.08 (m,
1H), 4.32-4.25 (m, 1H), 3.66 (s, 1.5H), 3.65 (s, 1.5H), 3.53-3.51
(m, 1H), 3.09-3.00 (m, 1H), 2.86 (d, J = 5.1 Hz, 1.5H), 2.66 (d, J
= 5.1 Hz, 1.5H), 2.48-2.20 (m, 2H), 2.11- 2.01 (m, 1H), 1.94-1.84
(m, 1H) 27 ##STR00187## 131 454 .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 7.64-7.55 (m, 2H), 7.49-7.34 (m, 6H),
6.95-6.87 (m, 1H), 6.10 (m, 1H), 5.96 (d, J = 2.7 Hz, 1H), 5.54 (d,
J = 5.3 Hz, 0.5H), 5.31 (d, J = 4.2 Hz, 0.5H), 5.14 (s, 2H),
4.83-4.76 (m, 0.5H), 4.70- 4.66 (m, 0.5H), 3.59 (s, 1.5 H), 3.58
(s, 1.5H), 3.32-3.29 (m, 1H), 2.76 (d, J = 16.3 Hz, 0.5H), 2.63 (d,
J = 15.9 Hz, 0.5H), 2.37-2.14 (m, 2H), 2.02-1.77 (m, 4H), 1.75-1.59
(m, 1H) 28 ##STR00188## 12 454 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.71 (d, J = 8.5 Hz, 0.3H), 7.68 (d, J = 8.5 Hz, 0.7H),
7.61-7.59 (m, 1H), 7.48-7.46 (m, 3H), 7.43- 7.42 (m, 2H), 7.41-7.36
(m, 1H), 7.09-7.08 (m, 1H), 6.35-6.32 (m, 1H), 6.16-6.15 (m, 1H),
5.40-5.38 (m, 1H), 4.91 (s, 2H), 4.71-4.53 (m, 1H), 3.72 (s, 3H),
3.56-3.47 (m, 1H), 3.42- 3.32 (m, 1H), 3.21-3.02 (m, 1H), 2.61-2.41
(m, 2H), 2.32-2.18 (m, 1H), 2.15-1.98 (m, 1H), 1.53-1.49 (m, 2H),
1.49-1.43 (m, 2H), 1.32- 1.26 (m, 2H) 29 ##STR00189## 75 473
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.62 (d, J = 2.5 Hz,
1H), 7.84-7.80 (m, 1H), 7.67-7.64 (m, 1H), 7.61-7.54 (m, 2H), 7.39
(m, 1H), 6.94- 6.91 (m, 1H), 6.12 (d, J = 7.0 Hz, 1H), 5.97 (s,
1H), 5.56-5.54 (m, 0.4H), 5.40-5.30 (m, 0.6H), 5.20 (s, 2H),
4.90-4.60 (m, 1H), 3.59 (s, 1.2H), 3.58 (s, 1.8H), 2.78 (d, J =
16.5 Hz, 0.4H), 2.65 (d, J = 16.0 Hz, 0.6H), 2.36-2.15 (m, 2H),
2.03-1.80 (m, 5H), 1.72-1.60 (m, 1H) 30 ##STR00190## 97 440 .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 9.49 (s, 0.3H), 9.14 (s, 0.7H),
7.43-7.26 (m, 8H), 6.93-6.91 (dd, J = 8.2, 1.8 Hz, 0.7H), 6.85-6.83
(dd, J = 8.2, 1.8 Hz, 0.3H), 6.09-6.05 (m, 2H), 5.58 (d, J = 5.4
Hz, 0.3H), 5.10-5.06 (m, 2.7H), 5.01- 4.58 (m, 0.7H), 4.48-4.30 (m,
0.3H), 3.39- 3.35 (dd, J = 16.1, 4.3 Hz, 0.7H), 3.13-3.09 (dd, J =
16.0, 4.0 Hz, 0.3H), 2.43 (d, J = 16.0 Hz, 0.7H), 2.38 (d, J = 16.0
Hz, 0.3H), 2.30- 2.06 (m, 5H), 2.05-1.95 (m, 1H), 1.89-1.75 (m,
0.3H), 1.61-1.52 (m, 0.7H) 31 ##STR00191## 14 440 .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 10.96
(s, 1H), 7.60-7.51 (m, 3H), 7.49-7.35 (m, 5H), 6.99-6.96 (dd, J =
8.3, 1.8 Hz, 1H), 6.12-6.09 (dd, J = 7.6, 2.7 Hz, 1H), 5.97 (d, J =
2.7 Hz, 1H), 5.15 (s, 2H), 5.02 (s, 1H), 3.98-3.93 (m, 1H), 3.70
(s, 3H), 3.43-3.35 (dd, J = 18.3, 7.3 Hz, 1H), 3.07 (d, J = 18.4
Hz, 1H), 2.65 (d, J = 4.9 Hz, 3H), 2.36-2.16 (m, 2H), 1.86 (d, J =
13.7 Hz, 1H), 1.74 (d, J = 13.4 Hz, 1H), 1.42 (d, J = 13.2 Hz, 1H),
1.26-1.14 (m, 1H) 32 ##STR00192## 15 454 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.46- 10.26 (s, 1H), 7.59-7.57 (m, 2H), 7.51
(d, J = 1.7 Hz, 1H), 7.48-7.46 (m, 2H), 7.44-7.41 (m, 2H),
7.39-7.37 (m, 1H), 6.98-6.96 (dd, J = 8.3, 1.8 Hz, 1H), 6.16-6.09
(dd, J = 7.6, 2.7 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.15 (s, 3H),
4.15-4.01 (m, 1H), 3.69 (s, 3H), 3.40 (dd, J = 18.2, 6.7 Hz, 1H),
3.09-3.04 (d, J = 18.2 Hz, 1H), 3.04-2.93 (m, 2H), 2.37-2.17 (m,
2H), 1.92-1.84 (d, J = 13.9 Hz, 1H), 1.75 (d, J = 13.8 Hz, 1H),
1.49-1.41 (m, 1H), 1.32-1.19 (m, 4H) 33 ##STR00193## 17 415 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.62 (d, J = 8.5 Hz, 1H), 7.44
(d, J = 2.0 Hz, 1H), 7.40- 7.35 (m, 4H), 7.32-7.28 (m, 1H), 7.08
(dd, J = 8.5, 2.0 Hz, 1H), 5.22 (d, J = 5.5 Hz, 1H), 4.55-4.52 (m,
1H), 4.30-3.80 (m, 6H), 3.70 (s, 3H), 3.63-3.59 (m, 2H), 3.52-3.47
(m, 1H), 3.22-3.18 (m, 2H), 3.08-3.04 (m, 1H), 2.47- 2.35 (m, 2H),
2.29-2.24 (m, 1H), 2.00-1.94 (m, 1H) 34 ##STR00194## 68% @ 1 uM 415
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.64 (d, J = 8.5 Hz, 1H),
7.44 (d, J = 1.5 Hz, 1H), 7.40- 7.35 (m, 4H), 7.32-7.28 (m, 1H),
7.08 (dd, J = 8.0, 1.5 Hz, 1H), 5.22 (d, J = 5.5 Hz, 1H), 4.55-4.52
(m, 1H), 4.30-3.80 (m, 6H), 3.70 (s, 3H), 3.62-3.58 (m, 2H), 3.50
(dd, J = 17.5, 4.5 Hz, 1H), 3.21-3.16 (m, 2H), 3.06 (d, J = 17.0
Hz, 1H), 2.49-2.34 (m, 2H), 2.29-2.24 (m, 1H), 2.00-1.97 (m, 1H) 35
##STR00195## 59 397 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.15
(d, J = 2.0 Hz, 1H), 8.85 (dd, J = 8.5, 2.5 Hz, 1H), 8.05 (d, J =
8.5 Hz, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H),
7.55 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.08 (d,
J = 2.0 Hz, 1H), 6.90 (dd, J = 7.0, 2.0 Hz, 1H), 5.26 (d, J = 5.0
Hz, 1H), 4.58-4.56 (m, 1H), 3.73 (s, 3H), 3.52 (dd, J = 17.0, 4.5
Hz, 1H), 3.10 (dd, J = 17.0, 1.0 Hz, 1H), 2.87 (s, 3H), 2.51-2.36
(m, 2H), 2.32-2.27 (m, 1H), 2.03-1.99 (m, 1H) 36 ##STR00196## 5.3
451 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.10 (s, 1H), 8.41
(d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.0 Hz,
1H), 7.71 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.15 (dd,
J = 8.0, 1.5 Hz, 1H), 7.02 (d, J = 1.5 Hz, 1H), 6.89 (dd, J = 7.0,
1.5 Hz, 1H), 5.26 (d, J = 5.0 Hz, 1H), 4.58-4.55 (m, 1H), 3.73 (s,
3H), 3.52 (dd, J = 17.5, 4.5 Hz, 1H), 3.10 (d, J = 17.0, 1H),
2.51-2.36 (m, 2H), 2.32-2.27 (m, 1H), 2.03- 1.99 (m, 1H) 37
##STR00197## 72% @ 1 uM 451 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.10 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 8.0, 2.0 Hz, 1H),
7.97 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.71 (d, J =
8.0 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.0, 1.5 Hz,
1H), 7.02 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 7.0, 2.0 Hz, 1H), 5.26
(d, J = 5.0 Hz, 1H), 4.57-4.54 (m, 1H), 3.73 (s, 3H), 3.52 (dd, J =
17.5, 5.0 Hz, 1H), 3.10 (dd, J = 17.0, 1.0 Hz, 1H), 2.51-2.36 (m,
2H), 2.32-2.28 (m, 1H), 2.04-2.01 (m, 1H) 38 ##STR00198## 12 481
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.16 (d, J
= 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H),
7.61 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.07 (dd, J =
8.5, 2.0 Hz, 1H), 6.35 (dd, J = 8.0, 3.0 Hz, 1H), 6.17 (d, J = 2.5
Hz, 1H), 5.36 (s, 2H), 5.24 (d, J = 5.5 Hz, 1H), 4.56-4.53 (m, 1H),
3.70 (s, 3H), 3.50 (dd, J = 17.0, 4.5 Hz, 1H), 3.08 (dd, J = 17.5,
1.5 Hz, 1H), 2.48-2.36 (m, 2H), 2.31-2.26 (m, 1H), 2.02-2.00 (m,
1H) 39 ##STR00199## 21 413 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.10 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H),
7.48-7.35 (m, 6H), 6.37 (dd, J = 7.5, 2.5 Hz, 1H), 6.15 (d, J = 2.5
Hz, 1H), 5.26 (d, J = 5.5 Hz, 1H), 5.21 (s, 2H), 4.58-4.55 (m, 1H),
3.75 (s, 3H), 3.54 (dd, J = 17.5, 4.5 Hz, 1H), 3.15-3.11 (dd, J =
17.5, 1.0 Hz, 1H), 2.51-2.36 (m, 2H), 2.33-2.28 (m, 1H), 2.04-2.02
(m, 1H) 40 ##STR00200## 49 446 .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.61 (d, J = 11.3 Hz, 1H), 9.13 (d, J = 10.7 Hz, 1H), 8.63
(d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.86-7.79 (m, 2H),
7.68-7.63 (dd, J = 8.6, 4.5 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H),
6.22-6.18 (dd, J = 7.7, 2.6 Hz, 1H), 6.00 (d, J = 2.6 Hz, 1H), 5.23
(s, 2H), 5.03 (s, 1H), 4.11-3.96 (m, 1H), 3.73 (s, 3H), 3.49-3.39
(dd, J = 18.3, 7.5 Hz, 1H), 3.16 (d, J = 18.2 Hz, 1H), 2.16-1.94
(m, 2H), 1.82 (d, J = 13.9 Hz, 1H), 1.72 (d, J = 13.9 Hz, 1H),
1.49-1.45 (m, 1H), 1.34-1.25 (m, 1H) 41 ##STR00201## 30 427 .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 9.52 (d, J = 10.6 Hz, 1H), 9.10
(d, J = 10.5 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.7
Hz, 1H), 7.49 (m, 6H), 6.19-6.15 (dd, J = 7.6, 2.7 Hz, 1H), 6.00
(dd, J = 2.7 Hz, 1H), 5.17 (s, 2H), 5.06 (s, 1H), 4.18-4.00 (m,
1H), 3.73 (s, 3H), 3.44-3.36 (dd, J = 18.3, 7.4 Hz, 1H), 3.09 (d, J
= 18.1 Hz, 1H), 2.15-2.00 (m, 2H), 1.83 (d, J = 13.3 Hz, 1H), 1.72
(d, J = 13.4 Hz, 1H), 1.49-1.45 (m, 1H), 1.34-1.14 (m, 1H) 42
##STR00202## 27 427 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.07
(d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.0, 3.5 Hz, 1H), 7.47 (d, J =
7.0 Hz, 2H), 7.40-7.39 (m, 2H), 7.34-7.36 (m, 2H), 6.32 (dd, J =
7.5, 2.5 Hz, 1H), 6.11 (d, J = 2.5 Hz, 1H), 5.19 (s, 2H), 5.18-5.10
(m, 1H), 4.39-4.35 (m, 1H), 3.79 (s, 1H), 3.76 (s, 2H), 3.63-3.50
(m, 1H), 3.18-3.15 (m, 1H), 2.99 (s, 2H), 2.86 (s, 1H), 2.66-2.50
(m, 2H), 2.35-2.29 (m, 1H), 2.11-2.06 (m, 1H) 43 ##STR00203## 38
432 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.54 (d, J = 2.5 Hz,
1H), 8.10 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.77-7.73
(m, 1H), 7.71-7.67 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.37 (dd, J =
7.5, 2.5 Hz, 1H), 6.13 (d, J = 2.5 Hz, 1H), 5.29 (s, 2H), 5.25 (d,
J = 5.0 Hz, 1H), 4.58-4.55 (m, 1H), 3.76 (s, 3H), 3.56-3.51 (dd, J
= 18.0, 5.0 Hz, 1H), 3.15-3.10 (dd, J = 17.5, 1.0 Hz, 1H),
2.51-2.29 (m, 3H), 2.05-2.01 (m, 1H) 44 ##STR00204## 110 452
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.11 (s, 1H), 8.42 (d, J
= 8.0 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 7.0 Hz, 1H),
7.98 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.03 (d, J =
1.5 Hz, 1H), 6.92 (dd, J = 7.5, 2.0 Hz, 1H), 5.28 (d, J = 5.0 Hz,
1H), 4.59 (m, 1H), 3.79 (s, 3H), 3.58-3.53 (dd, J = 17.5, 5.0 Hz,
1H), 3.17- 3.13 (d, J = 17.5 Hz, 1H), 2.52-2.31 (m, 3H), 2.06-2.03
(m, 1H) 45 ##STR00205## 26 449 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.10 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.59
(m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.07-7.02 (m, 2H), 6.29 (dd, J =
7.5, 2.5 Hz, 1H), 6.15 (d, J = 2.5 Hz, 1H), 5.40-5.25 (m, 1H), 5.20
(s, 2H), 4.70-4.50 (m, 1H), 3.76 (s, 3H), 3.55-3.51 (dd, J = 17.5,
4.5 Hz, 1H), 3.15-3.11 (d, J = 18.0 Hz, 1H), 2.51-2.29 (m, 3H),
2.05-1.99 (m, 1H) 46 ##STR00206## 99 450 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.03 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.0 Hz,
1H), 7.40- 7.34 (m, 4H), 5.22 (d, J = 5.5 Hz, 1H), 4.57- 4.54 (m,
1H), 4.40-4.20 (m, 4H), 4.00-3.80 (m, 2H), 3.74 (s, 3H), 3.60 (t, J
= 8.5 Hz, 2H), 3.54-3.50 (dd, J = 17.5, 4.5 Hz, 1H), 3.20-3.16 (m,
2H), 3.12-3.08 (d, J = 17.5 Hz, 1H), 2.50- 2.26 (m, 3H), 2.03-2.00
(m, 1H) 47 ##STR00207## 14 465 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.10 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.57-
7.53 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32- 7.28 (m, 2H), 6.30
(dd, J = 8.0, 3.0 Hz, 1H), 6.14 (d, J = 2.5 Hz, 1H), 5.26 (d, J =
5.5 Hz, 1H), 5.22 (s, 2H), 4.58-4.55 (m, 1H), 3.76 (s, 3H),
3.55-3.51 (dd, J = 17.5, 4.5 Hz, 1H), 3.15- 3.11 (d, J = 17.5 Hz,
1H), 2.51-2.29 (m, 3H), 2.05-2.01 (m, 1H) 48 ##STR00208## 28 481
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.10 (d, J = 8.0 Hz, 1H),
7.80 (d, J = 7.5 Hz, 1H), 7.59- 7.57 (m, 2H), 7.42 (dd, J = 8.5,
2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.32 (dd, J = 8.0, 2.5 Hz,
1H), 6.12 (d, J = 2.5 Hz, 1H), 5.25 (m, 3H), 4.58-4.56 (m, 1H),
3.76 (s, 3H), 3.55-3.51 (dd, J = 18.0, 4.5 Hz, 1H), 3.15-3.11 (d, J
= 17.5 Hz, 1H), 2.51-2.29 (m, 3H), 2.05-1.99 (m, 1H) 49
##STR00209## 53% @ 1 uM 452 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.06 (s, 1H), 8.30-8.27 (m, 1H), 8.23 (d, J = 8.5 Hz, 1H),
8.15 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.49 (d, J =
8.0 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.28 (dd, J = 7.0, 1.5 Hz,
1H), 5.28 (d, J = 5.5 Hz, 1H), 4.59-4.56 (m, 1H), 3.79 (s, 3H),
3.57-3.52 (dd, J = 17.5, 4.5 Hz, 1H), 3.17- 3.13 (d, J = 17.5 Hz,
1H), 2.52-2.31 (m, 3H), 2.06-2.03 (m, 1H) 50 ##STR00210## 19 451
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.15 (d, J = 8.0 Hz, 1H),
8.01 (d, J = 7.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.84 (d, J =
8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H),
6.89 (dd, J = 7.5, 2.0 Hz, 1H), 5.28 (d, J = 5.0 Hz, 1H), 4.59-4.56
(m, 1H), 3.79 (s, 3H), 3.57- 3.52 (dd, J = 17.5, 4.5 Hz, 1H),
3.17-3.13 (d, J = 17.5 Hz, 1H), 2.52-2.31 (m, 3H), 2.07-2.00 (m,
1H)
[0426] As compounds that bind strongly to MCH-1, compounds of
formula I are expected to be effective in reducing obesity.
[0427] The present invention is not limited to the compounds found
in the above examples, and many other compounds falling within the
scope of the invention may also be prepared using the procedures
set forth in the above synthetic schemes. The preparation of
additional compounds of formula (I) using these methods will be
apparent to one of ordinary skill in the chemical arts.
[0428] Although preferred embodiments have been depicted and
described in detail herein, it will be apparent to those skilled in
the relevant art that various modifications, additions,
substitutions, and the like can be made without departing from the
spirit of the invention and these are therefore considered to be
within the scope of the invention as defined in the claims which
follow.
* * * * *