U.S. patent application number 12/849500 was filed with the patent office on 2010-12-02 for fused bicycloheterocycle substituted azabicyclic alkane derivatives.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Murali Gopalakrishnan, Jianguo Ji, Tao Li, Christopher L. Lynch.
Application Number | 20100305089 12/849500 |
Document ID | / |
Family ID | 38662941 |
Filed Date | 2010-12-02 |
United States Patent
Application |
20100305089 |
Kind Code |
A1 |
Ji; Jianguo ; et
al. |
December 2, 2010 |
Fused Bicycloheterocycle Substituted Azabicyclic Alkane
Derivatives
Abstract
The invention relates to fused bicycloheterocycle substituted
azabicyclic alkane derivatives, compositions comprising such
compounds, and methods of treating conditions and disorders using
such compounds and compositions.
Inventors: |
Ji; Jianguo; (Libertyville,
IL) ; Li; Tao; (Grayslake, IL) ; Lynch;
Christopher L.; (Trevor, WI) ; Gopalakrishnan;
Murali; (Libertyville, IL) |
Correspondence
Address: |
PAUL D. YASGER;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD, DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
38662941 |
Appl. No.: |
12/849500 |
Filed: |
August 3, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11748527 |
May 15, 2007 |
|
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12849500 |
|
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|
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60802195 |
May 19, 2006 |
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Current U.S.
Class: |
514/210.16 ;
544/238; 546/113 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
21/04 20180101; A61P 37/06 20180101; A61P 25/14 20180101; C07D
451/14 20130101; A61P 39/02 20180101; A61P 17/00 20180101; A61P
9/00 20180101; A61P 29/00 20180101; A61P 25/24 20180101; A61P 17/02
20180101; A61P 37/02 20180101; A61P 25/04 20180101; A61P 31/04
20180101; A61P 37/00 20180101; A61P 15/08 20180101; A61P 15/00
20180101; A61P 25/02 20180101; A61P 25/18 20180101; A61P 43/00
20180101; A61P 25/00 20180101; A61P 21/02 20180101; A61P 19/02
20180101; A61P 25/28 20180101; A61P 31/00 20180101; C07D 451/08
20130101; C07D 519/00 20130101; A61P 19/00 20180101; A61P 1/00
20180101; A61P 1/06 20180101 |
Class at
Publication: |
514/210.16 ;
544/238; 546/113 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61P 25/18 20060101 A61P025/18; A61P 25/28 20060101
A61P025/28; A61P 25/00 20060101 A61P025/00; A61P 29/00 20060101
A61P029/00; A61P 15/08 20060101 A61P015/08; A61P 9/00 20060101
A61P009/00; A61P 19/02 20060101 A61P019/02; A61P 37/00 20060101
A61P037/00; A61P 25/24 20060101 A61P025/24; C07D 403/14 20060101
C07D403/14; C07D 409/14 20060101 C07D409/14; C07D 407/14 20060101
C07D407/14; C07D 471/22 20060101 C07D471/22 |
Claims
1. The compound of formula (I), ##STR00025## or a pharmaceutically
acceptable salt, ester, amide, or prodrug thereof, wherein n is 1,
2 or 3; A is N or N.sup.+-0.sup.-; R is hydrogen, alkyl,
cycloalkylalkyl and arylalkyl; L is selected from the group
consisting of O, S, and --N(R.sub.a)--; Ar.sup.1 is a 6-membered
aryl or 6-membered heteroaryl ring; and Ar.sup.2 is a bicyclic
heteroaryl; and R.sub.a is selected from the group consisting of
hydrogen, alkyl and alkylcarbonyl; provided that if Ar.sup.1 is
##STR00026## then L is O or S.
2. The compound of claim 1, wherein Ar.sup.1 is selected from the
group consisting of: ##STR00027## wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are independently selected from the
group consisting of acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl,
alkylsulfonyl, alkynyl, amino, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro,
thioalkoxy, --NR.sub.8R.sub.j, (NR.sub.8R.sub.j)alkyl,
(NR.sub.8R.sub.j)alkoxy, (NR.sub.8R.sub.j)carbonyl, and
(NR.sub.8R.sub.j)sulfonyl; R.sub.8 and R.sub.j are each
independently selected from the group consisting of hydrogen and
alkyl.
3. The compound of claim 1, wherein Ar.sub.2 is selected from the
group consisting of ##STR00028## ##STR00029## wherein Z.sub.1,
Z.sub.2, Z.sub.3 and Z.sub.4 are each independently nitrogen or are
carbon, wherein the carbon atom is optionally substituted with a
substituent selected from the group consisting of hydrogen,
halogen, alkyl, --OR.sub.c, -alkyl-OR.sub.c, --NR.sub.dR.sub.e, and
-alkyl-NR.sub.dR.sub.e; R.sub.b is selected from the group
consisting of hydrogen, alkyl and alkylcarbonyl; R.sub.c is alkyl;
R.sub.d and R.sub.e are each independently selected from the group
consisting of hydrogen and alkyl, R.sub.6 and R.sub.7 are each
independently selected from the group consisting of hydrogen,
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylsulfonyl, alkynyl, carboxy, cyano, formyl,
haloalkoxy, haloalkyl, halo, hydrogen, hydroxy, hydroxyalkyl,
mercapto, nitro, thio alkoxy, --NR.sub.8R.sub.j,
(NR.sub.8R.sub.j)alkyl, (NR.sub.8R.sub.j)alkoxy,
(NR.sub.8R.sub.j)carbonyl, and (NR.sub.8R.sub.j)sulfonyl; R.sub.8
and R.sub.j are each independently selected from the group
consisting of hydrogen and alkyl.
4. The compound of claim 2, wherein A is N; R is methyl or
hydrogen; L is O; n is 2; and Ar.sub.2 is selected from the group
of consisting of: ##STR00030##
5. The compound of claim 2, wherein A is N; R is methyl or
hydrogen; L is O; n is 2; Ar.sub.1 is ##STR00031##
6. The compound of claim 2, wherein A is N; R is methyl or
hydrogen; L is O; n is 2; Ar.sub.1 is ##STR00032## and Ar.sup.2 is
##STR00033##
7. The compound of claim 1, selected from the group consisting of:
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-
-indole;
(endo)-3-(6-benzo[b]thiophen-5-yl-pyridazin-3-yloxy)-8-methyl-8-a-
za-bicyclo[3.2.1]octane;
(endo)-3-[6-(benzofuran-5-yl)-pyridazin-3-yloxy]-8-methyl-8-aza-bicyclo[3-
.2.1]octane;
6-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-
-indole;
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin--
3-yl}-1H-indazole;
1-methyl-5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-
-3-yl}-1H-indole;
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2--
trifluoromethyl-1H-indole;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole;
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-y-
l}-1H-indole;
(endo)-3-(6-benzo[b]thiophen-5-yl-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo-
[3.2.1]octane;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole;
(exo)-3-[6-(benzofuran-5-yl)-pyridin-3-yloxy]-8-methyl-8-aza-bicyclo-
[3.2.1]loctane;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dazole;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl-
}-2-trifluoromethyl-1H-indole;
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole;
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-
-1H-indole;
(endo)-3-(5-benzo[b]thiophen-5-yl-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo-
[3.2.1]octane;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole;
[6-(1H-indol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.-
1]oct-3-yl]-amine;
[6-(benzofuran-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl]-amine;
[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(2-trifluoromethyl-1H-i-
ndol-5-yl)-pyridin-3-yl]-amine;
[6-(1H-indazol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl]-amine;
[6-(1H-indol-4-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl]-amine;
[(endo)-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(1H-indol-5-yl)-pyridin-3-yl]ami-
ne;
[4-(1H-indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3--
yl]-amine;
[4-(1H-indazol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2-
.1]oct-3-yl]-amine;
[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[4-(1-methyl-1H-indol-5-yl-
)-phenyl]-amine;
(4-benzo[b]thiophen-5-yl-phenyl)-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl]-amine;
[4-(benzofuran-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-y-
l]-amine;
[4-(1H-indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]-
oct-3-yl]-amine;
[3-(1H-indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-
-amine;
[3-(1H-indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oc-
t-3-yl]-amine;
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2--
trifluoromethyl-1H-indole;
4-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl-
}-1H-indole;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-2-tri-
fluoromethyl-1H-indole;
4-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole;
6-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl-
}-1H-indole;
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-i-
ndole;
4-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl-
}-1H}-indole;
6-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-i-
ndole;
[6-(1H-indol-6-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2-
.1]oct-3-yl]-amine;
5-{6-[(endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yloxy]pyridazin-3-yl}-1H-
-indole;
(endo)-3-[6-(benzo[b]thiophen-5-yl)pyridazin-3-yloxy]-9-methyl-9--
azabicyclo[3.3.1]nonane;
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-p-
yrrolo[2,3-b]pyridine;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-py-
rrolo[2,3-b]pyridine;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}--
1H-indole;
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-
-yl}-1H-indole;
6-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole.
(endo)-N-(5-(1H-Indol-5-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1-
]octan-3-amine
(endo)-N-(5-(1H-Indol-4-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octa-
n-3-amine
(endo)-N-(5-(1H-Indol-6-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3-
.2.1]octan-3-amine
(endo)-N-{5-[2-(trifluoromethyl)-1H-indol-5-yl]pyridin-3-yl}-8-Methyl-8-a-
zabicyclo[3.2.1]octan-3-amine;
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-p-
yrrolo[2,3-b]pyridine;
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indol-
in-2-one;
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-i-
ndole;
(1R,3r,5S,8s)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabi-
cyclo[3.2.1]octane8-oxide;
(1R,3r,5S,8r)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabicyclo[-
3.2.1]octane 8-oxide;
4-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indolin-2-one;
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,-
3-b]pyridine;
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3-
-b]pyridine.
8. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 in combination with a
pharmaceutically acceptable carrier.
9. A method of selectively modulating the effects of .alpha.7
nicotinic acetylcholine receptors, .alpha.4.beta.2 nicotinic
acetylcholine receptors, or both .alpha.7 and .alpha.4.beta.2
nicotinic acetylcholine receptors in a mammal comprising
administering an effective amount of a compound of claim 1.
10. A method of treating or preventing a condition or disorder
selected from the group consisting of attention deficit disorder,
attention deficit hyperactivity disorder (ADHD), Alzheimer's
disease (AD), mild cognitive impairment, senile dementia, AIDS
dementia, Pick's Disease, dementia associated with Lewy bodies,
dementia associated with Down's syndrome, amyotrophic lateral
sclerosis, Huntington's disease, diminished CNS function associated
with traumatic brain injury, acute pain, post-surgical pain,
chronic pain, inflammation, inflammatory pain, neuropathic pain,
infertility, need for new blood vessel growth associated with wound
healing, need for new blood vessel growth associated with
vascularization of skin grafts, and lack of circulation, rheumatoid
arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel
disease, organ transplant rejection, acute immune disease
associated with organ transplantation, chronic immune disease
associated with organ transplantation, septic shock, toxic shock
syndrome, sepsis syndrome, depression, and rheumatoid spondylitis,
comprising the step of administering a compound of claim 1.
11. The method according to claim 10, wherein the condition or
disorder is selected from the group consisting of a cognitive
disorder, neurodegeneration, and schizophrenia.
12. The method according to claim 10, further comprising
administering a compound of claim 1 in combination with an atypical
antipsychotic.
13. The method according to claim 10, further comprising
administering a compound of claim 1 in combination with a
medication used in the treatment of attention deficit hyperactivity
disorders and other cognitive disorders such as Alzheimer's
disease.
Description
RELATED APPLICATION INFORMATION
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/748,527, filed on May 15, 2007, which claims the
benefit of U.S. Provisional Patent Application No. 60/802,195 filed
on May 19, 2006, each of which are herein incorporated by reference
in its entirely.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The invention relates to fused bicycloheterocycle
substituted azabicyclic alkane derivatives, compositions comprising
such compounds, and methods of treating conditions and disorders
using such compounds and compositions.
[0004] 2. Description of Related Technology
[0005] Nicotinic acetylcholine receptors (nAChRs) are widely
distributed throughout the central (CNS) and peripheral (PNS)
nervous systems. Such receptors play an important role in
regulating CNS function, particularly by modulating release of a
wide range of neurotransmitters, including, but not necessarily
limited to acetylcholine, norepinephrine, dopamine, serotonin and
GABA. Consequently, nicotinic receptors mediate a very wide range
of physiological effects, and have been targeted for therapeutic
treatment of disorders relating to cognitive function, learning and
memory, neurodegeneration, pain and inflammation, psychosis and
sensory gating, mood and emotion, among others.
[0006] Many subtypes of the nAChR exist in the CNS and periphery.
Each subtype has a different effect on regulating the overall
physiological function. Typically, nAChRs are ion channels that are
constructed from a pentameric assembly of subunit proteins. At
least 12 subunit proteins, .alpha.2-.alpha.10 and .beta.2-.beta.4,
have been identified in neuronal tissue. These subunits provide for
a great variety of homomeric and heteromeric combinations that
account for the diverse receptor subtypes. For example, the
predominant receptor that is responsible for high affinity binding
of nicotine in brain tissue has composition
(.alpha.4).sub.2(.beta.2).sub.3 (the .alpha.4.beta.2 subtype),
while another major population of receptors is comprised of
homomeric (.alpha.7).sub.5 (the .alpha.7 subtype) receptors.
[0007] Certain compounds, like the plant alkaloid nicotine,
interact with all subtypes of the nAChRs, accounting for the
physiological effects of this compound. While nicotine has been
demonstrated to have many biological activities, not all of the
effects mediated by nicotine are desirable. For example, nicotine
exerts gastrointestinal and cardiovascular side effects that
interfere at therapeutic doses, and its addictive nature and acute
toxicity are well-known. Ligands that are selective for interaction
with only certain subtypes of the nAChR offer potential for
achieving beneficial therapeutic effects with an improved margin
for safety.
[0008] The .alpha.7 and .alpha.4.beta.2 nAChRs have been shown to
play a significant role in enhancing cognitive function, including
aspects of learning, memory and attention (Levin, E. D., J.
Neurobiol. 53: 633-640, 2002). For example, .alpha.7 nAChRs have
been linked to conditions and disorders related to attention
deficit disorder, attention deficit hyperactivity disorder (ADHD),
Alzheimer's disease (AD), mild cognitive impairment, senile
dementia, dementia associated with Lewy bodies, dementia associated
with Down's syndrome, AIDS dementia, Pick's Disease, as well as
cognitive deficits associated with schizophrenia, among other
systemic activities. The .alpha.4.beta.2 receptor subtype is
implicated in attention, cognition, schizophrenia, epilepsy, and
pain control (Paterson and Norberg, Progress in Neurobiology 61
75-111, 2000).
[0009] The activity at both .alpha.7 and .alpha.4.beta.2 nAChRs can
be modified or regulated by the administration of subtype selective
nAChR ligands. The ligands can exhibit antagonist, agonist, or
partial agonist properties. Compounds that function as positive
allosteric modulators are also known.
[0010] Although compounds that nonselectively demonstrate activity
at a range of nicotinic receptor subtypes including the
.alpha.4.beta.2 and .alpha.7 nAChRs are known, it would be
beneficial to provide compounds that interact selectively with
.alpha.7-containing neuronal nAChRs, .alpha.4.beta.2 nAChRs, or
both .alpha.7 and .alpha.4.beta.2 nAChRs compared to other
subtypes.
SUMMARY OF THE INVENTION
[0011] The invention is directed to fused bicycloheterocycle
substituted azabicyclic compounds as well as compositions
comprising such compounds, and method of using the same.
[0012] One aspect of the present invention is directed toward a
compound of formula (I)
##STR00001##
or a pharmaceutically acceptable salt, ester, amide, or prodrug
thereof, wherein
[0013] n is 1, 2 or 3;
[0014] A is N or N.sup.+-0.sup.-;
[0015] R is hydrogen, alkyl, cycloalkylalkyl and arylalkyl;
[0016] L is selected from the group consisting of O, S, and
--N(R.sub.a)--;
[0017] Ar.sup.1 is a 6-membered aryl or 6-membered heteroaryl
ring;
[0018] Ar.sup.2 is a bicyclic heteroaryl; and
[0019] R.sub.a is selected from the group consisting of hydrogen,
alkyl and alkylcarbonyl;
[0020] provided that if Ar.sup.1 is
##STR00002##
[0021] then L is O or S.
[0022] Another aspect of the invention relates to pharmaceutical
compositions comprising compounds of the invention. Such
compositions can be administered in accordance with a method of the
invention, typically as part of a therapeutic regimen for treatment
or prevention of conditions and disorders related to nAChR
activity, and more particularly .alpha.7 nAChR activity.
[0023] Yet another aspect of the invention relates to a method of
selectively modulating to nAChR activity, for example .alpha.7
nAChR activity. The method is useful for treating and/or preventing
conditions and disorders related to .alpha.7 nAChR activity
modulation in mammals. More particularly, the method is useful for
conditions and disorders related to attention deficit disorder,
attention deficit hyperactivity disorder (ADHD), Alzheimer's
disease (AD), mild cognitive impairment, senile dementia, AIDS
dementia, Pick's Disease, dementia associated with Lewy bodies,
dementia associated with Down's syndrome, amyotrophic lateral
sclerosis, Huntington's disease, diminished CNS function associated
with traumatic brain injury, acute pain, post-surgical pain,
chronic pain, inflammatory pain, neuropathic pain, infertility,
need for new blood vessel growth associated with wound healing,
need for new blood vessel growth associated with vascularization of
skin grafts, and lack of circulation, more particularly circulation
around a vascular occlusion, among other systemic activities, for
example inflammatory response mediated by TNF.
[0024] The compounds, compositions comprising the compounds, and
methods for treating or preventing conditions and disorders by
administering the compounds are further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0025] Certain terms as used in the specification are intended to
refer to the following definitions, as detailed below.
[0026] The term "acyl", as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through a
carbonyl group, as defined herein. Representative examples of acyl
include, but are not limited to, acetyl, 1-oxopropyl,
2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
[0027] The term "acyloxy", as used herein, means an acyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of acyloxy include, but are
not limited to, acetyloxy, propionyloxy, and isobutyryloxy.
[0028] The term "alkenyl", as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0029] The term "alkoxy", as used herein, means an alkyl group as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0030] The term "alkoxyalkoxy", as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through another alkoxy group, as defined herein. Representative
examples of alkoxyalkoxy include, but are not limited to,
tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and
methoxymethoxy.
[0031] The term "alkoxyalkyl", as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
[0032] The term "alkoxycarbonyl", as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, represented by --C(O)--, as defined
herein. Representative examples of alkoxycarbonyl include, but are
not limited to, methoxycarbonyl, ethoxycarbonyl, and
tert-butoxycarbonyl.
[0033] The term "alkoxyimino", as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an imino group, as defined herein. Representative examples
of alkoxyimino include, but are not limited to, ethoxy(imino)methyl
and methoxy(imino)methyl.
[0034] The term "alkoxysulfonyl", as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
[0035] The term "alkyl", as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 6 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
[0036] The term "alkylcarbonyl", as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and
1-oxopentyl.
[0037] The term "alkylcarbonyloxy", as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
[0038] The term "alkylsulfonyl", as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl.
[0039] The term "alkylthio", as used herein, means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of alkylthio include, but
are not limited, methylthio, ethylthio, tert-butylthio, and
hexylthio.
[0040] The term "alkynyl", as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0041] The term "amido", as used herein, means an amino,
alkylamino, or dialkylamino group appended to the parent molecular
moiety through a carbonyl group, as defined herein. Representative
examples of amido include, but are not limited to, aminocarbonyl,
methylaminocarbonyl, dimethylaminocarbonyl, and
ethylmethylaminocarbonyl.
[0042] The term "aryl", as used herein, means a monocyclic or
bicyclic aromatic ring system. Representative examples of aryl
include, but are not limited to, phenyl and naphthyl.
[0043] The aryl groups of this invention are substituted with 0, 1,
2, 3, 4, or 5 substituents independently selected from acyl,
acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl,
alkynyl, amino, carboxy, cyano, formyl, haloalkoxy, haloalkyl,
halo, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy,
--NR.sub.gR.sub.j, (NR.sub.gR.sub.j)alkyl, (NR.sub.gR.sub.j)alkoxy,
(NR.sub.gR.sub.j)carbonyl, and (NR.sub.gR.sub.j)sulfonyl, wherein
R.sub.g and R.sub.j are each independently selected from the group
consisting of hydrogen and alkyl.
[0044] The term "arylcarbonyl", as used herein, means an aryl
group, as defined herein, or a benzyl group appended to the parent
molecular moiety through a carbonyl group, represented by --C(O)--,
as defined herein. Representative examples of arylcarbonyl include,
but are not limited to, phenylcarbonyl and benzylcarbonyl.
[0045] The term "aryloxycarbonyl", as used herein, means an
aryl-O-- group, wherein the aryl of aryl-O-- is as defined herein,
or a benzyoxyl group appended to the parent molecular moiety
through a carbonyl group, represented by --C(O)--, as defined
herein. Representative examples of aryloxycarbonyl include, but are
not limited to, phenoxycarbonyl and benzyloxycarbonyl.
[0046] The term "arylsulfonyl", as used herein, means an aryl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of arylsulfonyl include, but are not limited to,
phenylsulfonyl, (methylaminophenyl)sulfonyl,
(dimethylaminophenyl)sulfonyl, and (naphthyl)sulfonyl.
[0047] The term "carbonyl", as used herein, means a --C(O)--
group.
[0048] The term "carboxy", as used herein, means a --CO.sub.2H
group.
[0049] The term "cyano", as used herein, means a --CN group.
[0050] The term "formyl", as used herein, means a --C(O)H
group.
[0051] The term "halo" or "halogen", as used herein, means --Cl,
--Br, --I or --F.
[0052] The term "haloalkoxy", as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, chloromethoxy,
2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
[0053] The term "haloalkyl", as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0054] The term "heteroaryl" means an aromatic five- or
six-membered ring containing 1, 2, 3, or 4 heteroatoms
independently selected from group consisting of nitrogen, oxygen
and sulfur. The heteroaryl groups are connected to the parent
molecular moiety through a carbon or nitrogen atom. Representative
examples of heteroaryl include, but are not limited to, furyl,
imidazolyl, indazolyl, benzothiozolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienyl, triazinyl, and triazolyl.
[0055] The heteroaryl groups of the invention are substituted with
0, 1, 2, or 3 substituents independently selected from alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl,
alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio,
alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo,
hydroxy, hydroxyalkyl, mercapto, nitro, --NR.sub.gR.sub.j,
(NR.sub.gR.sub.j)alkyl, (NR.sub.gR.sub.j)alkoxy,
(NR.sub.gR.sub.j)carbonyl, and (NR.sub.gR.sub.j)sulfonyl, wherein
R.sub.g and R.sub.j are each independently selected from the group
consisting of hydrogen and alkyl.
[0056] The term "bicyclic heteroaryl" refers to fused aromatic
nine- and ten-membered bicyclic rings containing 1, 2, 3, or 4
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulfur. The bicyclic heteroaryl groups are
connected to the parent molecular moiety through a carbon or
nitrogen atom. Representative examples of bicyclic heteroaryl rings
include, but are not limited to, indolyl, benzothiazolyl,
benzofuranyl, isoquinolinyl, and quinolinyl. Bicyclic heteroaryl
groups of the invention are substituted with 0, 1, 2, or 3
substituents independently selected from alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,
carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy,
hydroxyalkyl, mercapto, nitro, --NR.sub.gR.sub.j,
(NR.sub.gR.sub.j)alkyl, (NR.sub.gR.sub.j)alkoxy,
(NR.sub.gR.sub.j)carbonyl, and (NR.sub.gR.sub.j)sulfonyl, wherein
R.sub.g and R.sub.j are each independently selected from the group
consisting of hydrogen and alkyl.
[0057] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic heterocycle or a bicyclic heterocycle. The
monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring
containing at least one heteroatom independently selected from the
group consisting of nitrogen, oxygen and sulfur. The 3 or 4
membered ring contains 1 heteroatom selected from the group
consisting of nitrogen, oxygen and sulfur. The 5 membered ring
contains zero or one double bond and one, two or three heteroatoms
selected from the group consisting of nitrogen, oxygen and sulfur.
The 6 or 7 membered ring contains zero, one or two double bonds and
one, two or three heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur. The monocyclic heterocycle is
connected to the parent molecular moiety through any carbon atom or
any nitrogen atom contained within the monocyclic heterocycle.
Representative examples of monocyclic heterocycle include, but are
not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,
1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,
oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,
piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl,
and trithianyl. The bicyclic heterocycle is a monocyclic
heterocycle that is either fused to a cycloalkyl ring, a heteroaryl
ring or another heterocyclic ring, or is formed by an alkyl chain
attached to two non-adjacent carbons contained within the
monocyclic heterocyclic ring. The bicyclic heterocycle is connected
to the parent molecular moiety through any carbon atom or any
nitrogen atom contained within the monocyclic heterocycle.
Representative examples of bicyclic heterocycle include, but are
not limited to, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane,
1,3-benzodioxolyl, 1,3-benzodithiolyl,
2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl,
2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and
1,2,3,4-tetrahydroquinolinyl.
[0058] The heterocyclic groups of the invention are substituted
with 0, 1, 2, or 3 substituents independently selected from
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,
alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl,
haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto,
nitro, --NR.sub.gR.sub.j, (NR.sub.gR.sub.j)alkyl,
(NR.sub.gR.sub.j)alkoxy, (NR.sub.gR.sub.j)carbonyl, and
(NR.sub.gR.sub.j)sulfonyl, wherein R.sub.g and R.sub.j are each
independently selected from the group consisting of hydrogen and
alkyl.
[0059] The term "hydroxy", as used herein, means an --OH group.
[0060] The term "hydroxyalkyl", as used herein, means at least one
hydroxy group, as defined herein, is appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not
limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
[0061] The term "mercapto", as used herein, means a --SH group.
[0062] The term "nitro", as used herein, means a --NO.sub.2
group.
[0063] The term "--NR.sub.gR.sub.j", as used herein, means two
groups, R.sub.g and R.sub.j which are appended to the parent
molecular moiety through a nitrogen atom. R.sub.g and R.sub.j are
each independently hydrogen or alkyl. Representative examples of
--NR.sub.gR.sub.j include, but are not limited to, amino,
methylamino, dimethylamino, and methylethylamino.
[0064] The term "(NR.sub.gR.sub.j)alkyl", as used herein, means a
--NR.sub.gR.sub.j group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of (NR.sub.gR.sub.j)alkyl include, but are
not limited to, (amino)methyl, (dimethylamino)methyl, and
(ethylamino)methyl.
[0065] The term "(NR.sub.gR.sub.j)alkoxy", as used herein, means a
--NR.sub.gR.sub.j group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of (NR.sub.gR.sub.j)alkoxy include, but are
not limited to, (amino)methoxy, (dimethylamino)methoxy, and
(diethylamino)ethoxy.
[0066] The term "(NR.sub.gR.sub.j)carbonyl", as used herein, means
a --NR.sub.gR.sub.j group, as defined herein, appended to the
parent molecular moiety through a carbonyl group, as defined
herein. Representative examples of (NR.sub.gR.sub.j)carbonyl
include, but are not limited to, aminocarbonyl,
(methylamino)carbonyl, (dimethylamino)carbonyl, and
(ethylmethylamino)carbonyl.
[0067] The term "(NR.sub.gR.sub.j)sulfonyl", as used herein, means
a --NR.sub.gR.sub.j group, as defined herein, appended to the
parent molecular moiety through a sulfonyl group, as defined
herein. Representative examples of (NR.sub.gR.sub.j)sulfonyl
include, but are not limited to, aminosulfonyl,
(methylamino)sulfonyl, (dimethylamino)sulfonyl, and
(ethylmethylamino)sulfonyl.
[0068] The term "sulfonyl", as used herein, means a --S(O).sub.2--
group.
[0069] The term "thioalkoxy", as used herein, means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of thioalkoxy include, but
are no limited to, methylthio, ethylthio, and propylthio.
[0070] Although typically it may be recognized that an asterisk is
used to indicate that the exact subunit composition of a receptor
is uncertain, for example .alpha.3.beta.4* indicates a receptor
that contains the .alpha.3 and .beta.4 proteins in combination with
other subunits, the term .alpha.7 as used herein is intended to
include receptors wherein the exact subunit composition is both
certain and uncertain. For example, as used herein .alpha.7
includes homomeric (.alpha.7).sub.5 receptors and .alpha.7*
receptors, which denote a nAChR containing at least one .alpha.7
subunit.
Compounds of the Invention
[0071] Compounds of the invention have the formula (I) as described
above. More particularly, compounds of formula (I) can include, but
are not limited to, compounds wherein A is N, and n is 1 or 2.
Certain preferred compounds exist wherein A is N; L is O; n is
2.
[0072] More particularly, in compounds of formula (I) Ar.sup.1 is
selected from:
##STR00003##
[0073] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
independently acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl,
alkylsulfonyl, alkynyl, amino, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro,
thioalkoxy, --NR.sub.gR.sub.j, (NR.sub.gR.sub.j)alkyl,
(NR.sub.gR.sub.j)alkoxy, (NR.sub.gR.sub.j)carbonyl, or
(NR.sub.gR.sub.j)sulfonyl; R.sub.g and R.sub.j are each
independently hydrogen or alkyl. More preferably, Ar.sup.1 is
##STR00004##
Particularly, the invention includes, but is not limited to,
compounds of formula (I) wherein A is N; R is methyl; L is O; n is
2; Ar.sup.1 is
##STR00005##
[0074] Ar.sup.2 in compounds of formula (I) is selected from:
##STR00006## ##STR00007##
[0075] wherein Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 are each
independently nitrogen or are carbon, wherein the carbon atom is
optionally substituted with a substituent selected from the group
consisting of hydrogen, halogen, alkyl, --OR.sub.c,
-alkyl-OR.sub.c, --NR.sub.dR.sub.e, and -alkyl-NR.sub.dR.sub.e;
R.sub.b is selected from the group consisting of hydrogen, alkyl
and alkylcarbonyl; R.sub.c is alkyl; R.sub.d and R.sub.e are each
independently selected from the group consisting of hydrogen and
alkyl, R.sub.6 and R.sub.7 are each independently selected from the
group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkynyl, carboxy,
cyano, formyl, haloalkoxy, haloalkyl, halo, hydrogen, hydroxy,
hydroxyalkyl, mercapto, nitro, thioalkoxy, --NR.sub.gR.sub.j,
(NR.sub.gR.sub.j)alkyl, (NR.sub.gR.sub.j)alkoxy,
(NR.sub.gR.sub.j)carbonyl, and (NR.sub.gR.sub.j)sulfonyl; R.sub.g
and R.sub.j are each independently selected from the group
consisting of hydrogen and alkyl.
[0076] R is selected from hydrogen, alkyl, cycloalkylalkyl, and
arylalky. Preferred compounds are disclosed wherein R is hydrogen
and alkyl. Preferably, R is methyl and hydrogen.
[0077] Preferred compounds are disclosed wherein Ar.sup.2 is
##STR00008##
More preferably Ar.sup.2 is
##STR00009##
Particularly, the invention relates to compounds of formula (I)
wherein A is N; R is selected from methyl and hydrogen; L is O; n
is 2; and Ar.sup.2 is selected from the group of consisting of:
##STR00010##
More particularly, the invention relates to compounds of formula
(I) wherein A is N; R is methyl or hydrogen; L is O; n is 2;
Ar.sup.1 is
##STR00011##
and
Ar.sup.2 is
##STR00012##
[0079] Compounds for the method of the invention, including but not
limited to those specified in the examples or otherwise
specifically named, can modulate, and often possess an affinity
for, nAChRs, and more particularly .alpha.7 nAChRs. As .alpha.7
nAChRs ligands, the compounds of the invention can be useful for
the treatment or prevention of a number of .alpha.7 nAChR-mediated
diseases or conditions.
[0080] Specific examples of compounds that can be useful for the
treatment or prevention of .alpha.7 nAChR-mediated diseases or
conditions include, but are not limited to, compounds described in
the Compounds of the Invention and also in the Examples, and also
compounds such as: [0081]
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-
-indole; [0082]
(endo)-3-(6-benzo[b]thiophen-5-yl-pyridazin-3-yloxy)-8-methyl-8-aza-bicyc-
lo[3.2.1]octane; [0083]
(endo)-3-[6-(benzofuran-5-yl)-pyridazin-3-yloxy]-8-methyl-8-aza-bicyclo[3-
.2.1]octane; [0084]
6-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-
-indole; [0085]
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-
-indazole; [0086]
1-methyl-5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-
-3-yl}-1H-indole; [0087]
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2--
trifluoromethyl-1H-indole; [0088]
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole; [0089]
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-i-
ndole; [0090]
(endo)-3-(6-benzo[b]thiophen-5-yl-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo-
[3.2.1]octane; [0091]
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole; [0092]
(exo)-3-[6-(benzofuran-5-yl)-pyridin-3-yloxy]-8-methyl-8-aza-bicyclo[3.2.-
1]octane; [0093]
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dazole; [0094]
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-2-tri-
fluoromethyl-1H-indole; [0095]
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole; [0096]
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-i-
ndole; [0097]
(endo)-3-(5-benzo[b]thiophen-5-yl-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo-
[3.2.1]octane; [0098]
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole; [0099]
[6-(1H-indol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl-]amine; [0100]
[6-(benzofuran-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl]-amine; [0101]
[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(2-trifluoromethyl-1H-i-
ndol-5-yl)-pyridin-3-yl]-amine; [0102]
[6-(1H-indazol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl]-amine; [0103]
[6-(1H-indol-4-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl]-amine; [0104]
[(endo)-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(1H-indol-5-yl)-pyridin-3-yl]-am-
ine; [0105]
[4-(1H-indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-
-amine; [0106]
[4-(1H-indazol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-y-
l]-amine; [0107]
[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[4-(1-methyl-1H-indol-5-yl-
)-phenyl]-amine; [0108]
(4-benzo[b]thiophen-5-yl-phenyl)-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl]-amine; [0109]
[4-(benzofuran-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-y-
l]-amine; [0110]
[4-(1H-indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-
-amine; [0111]
[3-(1H-indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-
-amine; [0112]
[3-(1H-indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-
-amine; [0113]
5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2--
trifluoromethyl-1H-indole; [0114]
4-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole; [0115]
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole; [0116]
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-2-tri-
fluoromethyl-1H-indole; [0117]
4-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole; [0118]
6-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole; [0119]
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-i-
ndole; [0120]
4-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-i-
ndole; [0121]
6-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-i-
ndole; [0122]
[6-(1H-indol-6-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl]-amine; [0123]
5-{6-[(endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yloxy]pyridazin-3-yl}-1H-
-indole; [0124]
(endo)-3-[6-(benzo[b]thiophen-5-yl)pyridazin-3-yloxy]-9-methyl-9-azabicyc-
lo[3.3.1]nonane; [0125]
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-p-
yrrolo[2,3-b]pyridine; [0126]
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-py-
rrolo[2,3-b]pyridine; [0127]
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole; [0128]
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole; [0129]
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole; [0130]
6-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole; [0131]
(endo)-N-(5-(1H-Indol-5-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octa-
n-3-amine;
[0132]
(endo)-N-(5-(1H-Indol-4-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.-
1]octan-3-amine; [0133]
(endo)-N-(5-(1H-Indol-6-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octa-
n-3-amine; [0134]
(endo)-N-{5-[2-(trifluoromethyl)-1H-indol-5-yl]pyridin-3-yl}-8-Methyl-8-a-
zabicyclo[3.2.1]octan-3-amine; [0135]
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-p-
yrrolo[2,3-b]pyridine; [0136]
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indol-
in-2-one; [0137]
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
[0138]
(1R,3r,5S,8s)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azab-
icyclo[3.2.1]octane 8-oxide; [0139]
(1R,3r,5S,8r)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabicyclo[-
3.2.1]octane 8-oxide; [0140]
4-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
[0141]
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indo-
le; [0142]
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indo-
lin-2-one; [0143]
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,-
3-b]pyridine; [0144]
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3-
-b]pyridine, or pharmaceutically acceptable salts, esters, amides,
and prodrugs thereof.
[0145] Compound names are assigned by using AUTONOM naming
software, which is provided by MDL Information Systems GmbH
(formerly known as Beilstein Informationssysteme) of Frankfurt,
Germany, and is part of the CHEMDRAW.RTM. ULTRA v. 6.0.2 software
suite.
[0146] Compounds of the invention may exist as stereoisomers
wherein, asymmetric or chiral centers are present. These
stereoisomers are "R" or "S" depending on the configuration of
substituents around the chiral element. The terms "R" and "S" used
herein are configurations as defined in IUPAC 1974 Recommendations
for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976,
45: 13-30.
##STR00013##
[0147] The attachment of L to the azabicyclic alkane may be
considered to encompass both the endo and exo geometries, such as
isomer (Ia) and (Ib). The configurational assignment of structures
of formula (Ia) are assigned endo in accordance with that described
in Stereochemistry of Organic Compounds, E. L. Eliel, S. H. Wilen;
John Wiley and Sons, Inc. 1994. Structures of formula (Ib) are
assigned exo using the same methods.
##STR00014##
[0148] The N.sup.+-0.sup.- portion of isomer (Ic) and isomer (Id)
are diastereomers. The configurational assignment of structures of
formula (Ic) are assigned (r) in accordance with that described in
Synthesis, 1992, 1080, Becker, D. P.; Flynn, D. L. and as defined
in Stereochemistry of Organic Compounds, E. L. Eliel, S. H. Wilen;
John Wiley and Sons, Inc. 1994. In addition the configurational
assignment of structures of formula (Id) are assigned (s) using the
same methods.
[0149] The invention contemplates various stereoisomers and
mixtures thereof and are specifically included within the scope of
this invention. Stereoisomers include enantiomers and
diastereomers, and mixtures of enantiomers or diastereomers.
Individual stereoisomers of compounds of the invention may be
prepared synthetically from commercially available starting
materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and optional
liberation of the optically pure product from the auxiliary as
described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's
Textbook of Practical Organic Chemistry", 5th edition (1989),
Longman Scientific & Technical, Essex CM20 2JE, England, or (2)
direct separation of the mixture of optical enantiomers on chiral
chromatographic columns or (3) fractional recrystallization
methods.
Methods for Preparing Compounds of the Invention
[0150] The reactions exemplified in the schemes are performed in a
solvent appropriate to the reagents and materials employed and
suitable for the transformations being effected. The described
transformations may require modifying the order of the synthetic
steps or selecting one particular process scheme over another in
order to obtain a desired compound of the invention, depending on
the functionality present on the molecule.
[0151] The methods described below can entail use of various
enantiomers. Where the stereochemistry is shown in the Schemes, it
is intended for illustrative purposes only.
##STR00015##
[0152] Compounds of formula (8), wherein Ar.sup.1, Ar.sup.2 are as
defined in formula (I), can be prepared as described in Scheme 1.
Compounds of formula (1) when treated with a compound of formula
(2a), wherein halo is bromide, chloride, or iodide, in the presence
of CuI, 1,10-phenanthroline and Cs.sub.2CO.sub.3 in a solvent such
as, but not limited to, toluene as described in Org. Lett., 2002,
4, 973, will provide compounds of formula (3). Compounds of formula
(3) can also be prepared through the reaction of compounds of
formula (1) with compounds of formula (2b) in the presence of a
base, such as, but not limited to, KHMDS, in a solvent such as but
not limited to THF, DME and toluene. Compounds of formula (3) when
treated with hexamethylditin or an organo-borane compound of
formula (4), such as bis(pinacolato)diboron or
bis(catecholato)diboron, wherein R is hydrogen, alkyl or aryl, in
the presence of a palladium catalyst will provide the corresponding
tin or boronic acid of formula (5), wherein M is --Sn-(Me).sub.3 or
--B(OR).sub.2. Compounds of formula (5) when treated with compounds
of formula (6), Ar.sub.2-halo, wherein Ar.sub.2 is a bicyclic
heteroaryl ring and halo is bromide, chloride, or iodide, in the
presence of a palladium catalyst to provide compounds of formula
(8). Alternatively, compounds of formula (6) when treated with
hexamethylditin or a di-borane containing compound of formula (4),
such as bis(pinacolato)diboron and bis(catecholato)diboron, in the
presence of a palladium catalyst will provide a corresponding tin
or boronic acid containing compound of formula (7), wherein
Ar.sub.2 is a bicyclic heteroaryl and wherein M is --Sn-(Me).sub.3
or --B(OR).sub.2. Compounds of formula (7) when treated with a
compound of formula (3) in the presence of a palladium catalyst
will provide a compound of formula (8).
##STR00016##
[0153] Compounds of formula (13), wherein Ar.sup.1 is a
nitrogen-containing heteroaryl, for examples pyridazine,
pyrimidine, pyrazine, 2-pyridyl, and Ar.sup.2 is as defined for
formula (I), can be prepared as shown in Scheme 2. Compounds of
formula (9), wherein R.sup.z is alkoxyalkyl, alkyl,
alkyloxycarbonyl, alkylcarbonyl, aryl, arylalkyloxycarbonyl,
cycloalkylalkyl, arylcarbonyl and aryloxycarbonyl and K represents
the potassium, which are prepared from treating hydroxyl containing
heterocycles of similar formula with potassium tert-butoxide in
solvents such as but not limited to THF or DMF to provide the
potassium oxide containing compounds of formula (9). The compounds
of formula (9) when treated with compounds of formula (10), wherein
Y.sup.1 and halo are both bromo, chloro and iodo, and X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 are independently either carbon or
nitrogen, for example, dichloropyridazine, will provide compounds
of formula (11). Compounds of formula (11) when treated with
hexamethylditin or a di-borane containing compound of formula (4)
in the presence of a palladium catalyst according to the procedure
outlined in Scheme 1 will provide compounds of formula (12).
Compounds of formula (12) treated with compounds of formula 6 in
the presence of a palladium catalyst will provide compounds of
formula (13). Alternatively, the compounds of formula (11) when
treated with organo stannane or organo boronic acid containing
compounds of formula (7), as described in Scheme 1, in the presence
of a palladium catalyst will provide a compound of formula
(13).
##STR00017##
[0154] Alternatively, compounds of formula (8) may be prepared as
outlined in Scheme 3. Compounds of formula (1) when treated with a
compound of formula (14), wherein Z.sup.3 is bromo, chloro or iodo
or is Ar.sup.2, in the presence of diethyl azodicarboxylate or
di(isopropyl) 1 azodicarboxylate and a phosphine, such as
triphenylphosphine, will provide compounds of formula (15). When
Z.sup.3 is Ar.sup.2, compounds of formula (15) are representative
of the present invention. When Z.sup.3 is a halogen, the further
treatment of the compound according to conditions outlined in
Schemes 1-2 outlining the Suzuki type coupling to provide compounds
of formula (8) which are representative of the compounds of the
present invention.
##STR00018##
[0155] Another method of generating compounds of formula (8) is
described in Scheme 4. The activated tin or boronic acid compounds
of formula (7) can be coupled with a variety of aryl halides that
will provide a method of generating biaryl compounds of formula
(17) and of formula (20). For example compounds of formula (7) when
treated with diiodobenzene of formula (16) in the presence of a
palladium catalyst will provide compounds of formula (17).
Compounds of formula (17) when treated with compounds of formula
(1) in the presence of cuprous iodide and cesium carbonate and
1,10-phenanthroline as described in Scheme 1, will provide
compounds of formula (8). Alternatively, compounds of formula (7)
when treated with a compound of formula (18), wherein R.sup.a is
benzyl or another appropriate alcohol protecting group, in the
presence of a palladium catalyst will provide compounds of formula
(19). The deprotection of the alcohol protecting group, for example
when R.sup.a is benzyl the deprotection is generally achieved
utilizing palladium on carbon and an atmosphere of hydrogen, will
provide compounds of formula (20). Compounds of formula (20) when
treated with compounds of formula (1) in the presence of
triphenylphosphine and diethyldiazocarboxylate or a similar reagent
will provide compounds of formula (8).
##STR00019##
[0156] Compounds of formula (25), which are representative of
compounds of formula (I), wherein L is --NH--, can be prepared as
shown in Scheme 5. Compounds of formula (21) when treated with
compounds of formula (22), wherein halo is bromide, chloride, or
iodide, along with sodium triacetoxy borohydride and
Na.sub.2SO.sub.4 in acetic acid will provide compounds of formula
(23). Alternatively, a compound of formula (23) can be obtained by
treating compounds of formula (24) with a compound of formula (2),
wherein Y is bromo or iodo, in the presence of palladium catalyst,
preferably in toluene. Compounds of formula (23) when further
treated with a tin or diboron of formula (4), such as
bis(pinacolato)diboron and bis(catecholato)diboron, under
conditions described in Scheme 2, will provide the corresponding
tin or boronic acid compounds of formula (26). Compounds of formula
(26) when treated with a compound of formula (6) in the presence of
a palladium catalyst, will provide the compound of formula (25).
Alternatively, the compound of formula (23) when treated with a tin
or boronic acid containing compound of formula (7) in the presence
of a palladium catalyst will also provide compounds of formula
(25).
##STR00020##
[0157] In addition, compounds of formula (25) can be prepared as
shown in Scheme 6. Ketone containing compounds of formula (21),
when treated with compounds of formula (27), prepared via the
coupling reaction of haloarylamine of formula (22) and a suitable
tin or boron agent of formula (7) in the presence of a palladium
catalyst, followed by treatment with sodium triacetate borohydride
and Na.sub.2SO.sub.4 in acetic acid will provide compounds of
formula (25) as described in Tetrahedron Lett. 1996, 37, 6045.
##STR00021##
[0158] Compounds of formula (31), wherein L is S and Ar.sup.1 and
Ar.sup.2 are as defined in formula (I), can be prepared as shown in
Scheme 7. Compounds of formula (29), wherein halo is bromide,
chloride, or iodide, when pretreated with sodium hydride in a
solvent such as but not limited to DMF followed by treatment with
compounds of formula (28) will provide compounds of formula (30).
Compounds of formula (30) when treated with a compound of formula
(7) as described in Scheme 1, will provide compounds of formula
(31), which are representative of compounds of formula (I) wherein
L is S. Alternatively, the compound of formula (30) when treated
with a hexamethylditin or diboron reagent of formula (4), such as
bis(pinacolato)diboron and bis(catecholato)diboron, in the presence
of a palladium catalyst will provide a compound of formula (32).
Compounds of formula (32) when treated with compounds of formula
(6), wherein halo is bromo, chloro or iodo, in the presence of a
palladium catalyst will provide compounds of formula (31).
##STR00022##
[0159] Compounds of formula (35) which are representative of
compounds of formula (I), wherein L is O, S, or --N(R.sub.a)--,
Ar.sup.1 is as previously defined in formula (I), and Ar.sup.2 is
an aminosubstituted benzothiazole are prepared according to the
conditions outlined in Scheme 8. Compounds of formula (33) which
are obtained by methods described in Schemes 1-7, wherein Ar.sup.2
is substituted with --NH.sub.2, when treated with bromine and KSCN
in acetic acid will provide compounds of formula (34). Compounds of
formula (34) can be further treated with the halide of a desired
R.sup.g group, wherein R.sup.g is as defined under the scope
compounds of the present invention to provide compounds of formula
(35).
##STR00023##
[0160] Compounds of formula (39), wherein L is O, NH, or S;
Ar.sup.1 is as previously defined in formula (I), Ar.sup.2 is a
benzoimidazole as defined for compounds of formula (I), are
prepared as outlined in Scheme 9. Compounds of formula (36), are
obtained by treating compounds of formula (33) of Scheme 8, using
conditions known to one skilled in the art that will incorporate a
nitrogen-protecting group to the nitrogen atom of Ar.sup.2 wherein
P is tert-butyloxycarbonyl, benzyloxycarbonyl, alkoxycarbonyl,
alkylcarbonyl, arylcarbonyl or trialkylsilane. Compounds of formula
(36) when treated with nitric acid in sulfuric acid will provide
compounds of formula (37). Compounds of formula (37) when subjected
to reducing conditions such as but not limited to treatment with a
palladium catalyst and an atmosphere of hydrogen will reduce the
nitro group to the corresponding amine, which is subjected to
conditions known to one skilled in the art that will remove the
nitrogen protecting group to provide compounds of formula (38).
Compounds of formula (38) were then further subjected to treatment
with an excess of an orthoester of formula (EtO).sub.3CR.sup.m will
provide compounds of formula (39) wherein R.sup.m is alkyl or
aryl.
##STR00024##
[0161] Benzooxazole-containing compounds of formula (44), wherein L
is O, NH, or S, Ar.sup.1 is as previously defined in formula (I),
and R.sup.n is alkyl hydrogen, or aryl, can be prepared as outlined
in Scheme 10. Compounds of formula (40) can be treated with a ditin
or diboron reagent of formula (4), such as hexamethylditin,
bis(pinacolato)diboron and bis(catecholato)diboron, in the presence
of a palladium catalyst to provide the corresponding tin or boronic
acid of formula (41). Compounds of formula (41) when treated with a
halogen containing compound of formula (42) in the presence of a
palladium catalyst will provide compounds of formula (43).
Compounds of formula (43) when treated according to conditions
known to one skilled in the art that will reduce nitro groups to
the corresponding amine group, followed by treatment with a R.sup.n
substituted ortho ester, wherein R.sup.n is hydrogen, alkyl or aryl
will provide compounds of formula (44).
[0162] In addition, compounds of formula (I) wherein A is N can be
converted to compounds of formula (I) wherein A is N.sup.+--O.sup.-
by treatment with an oxidizing agent. Examples of the oxidizing
agent include, but not limited to, aqueous hydrogen peroxide and
m-chloroperbenzoic acid. The reaction is generally performed in a
solvent such as, but not limited to, acetonitrile, water,
dichloromethane, acetone or mixture thereof, preferably a mixture
of acetonitrile and water, at a temperature from about 0.degree. C.
to about 80.degree. C., for a period of about 1 hour to about 4
days.
[0163] The compounds and intermediates of the invention may be
isolated and purified by methods well known to those skilled in the
art of organic synthesis. Examples of conventional methods for
isolating and purifying compounds can include, but are not limited
to, chromatography on solid supports such as silica gel, alumina,
or silica derivatized with alkylsilane groups, by recrystallization
at high or low temperature with an optional pretreatment with
activated carbon, thin-layer chromatography, distillation at
various pressures, sublimation under vacuum, and trituration, as
described for instance in "Vogel's Textbook of Practical Organic
Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and
Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE,
England.
[0164] The compounds of the invention have at least one basic
nitrogen whereby the compound can be treated with an acid to form a
desired salt. For example, a compound may be reacted with an acid
at or above room temperature to provide the desired salt, which is
deposited, and collected by filtration after cooling. Examples of
acids suitable for the reaction include, but are not limited to
tartaric acid, lactic acid, succinic acid, as well as mandelic,
atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic,
naphthalenesulfonic, carbonic, fumaric, gluconic, acetic,
propionic, salicylic, hydrochloric, hydrobromic, phosphoric,
sulfuric, citric, or hydroxybutyric acid, camphorsulfonic, malic,
phenylacetic, aspartic, glutamic, and the like.
[0165] Nitrogen protecting groups can be used for protecting amine
groups present in the described compounds. Such methods, and some
suitable nitrogen protecting groups, are described in Greene and
Wuts (Protective Groups In Organic Synthesis, Wiley and Sons,
1999). For example, suitable nitrogen protecting groups include,
but are not limited to, tert-butoxycarbonyl (Boc),
benzyloxycarbonyl (Cbz), benzyl (Bn), acetyl, and trifluoracetyl.
More particularly, the Boc protecting group may be removed by
treatment with an acid such as trifluoroacetic acid or hydrochloric
acid. The Cbz and Bn protecting groups may be removed by catalytic
hydrogenation. The acetyl and trifluoracetyl protecting groups may
be removed by a hydroxide ion.
[0166] The compounds and processes of the invention will be better
understood by reference to the following Examples, which are
intended as an illustration of and not a limitation upon the scope
of the invention.
Example 1
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole trifluoroacetate
Example 1A
(endo)-3-(6-chloro-pyridazin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0167] A mixture of (endo)-tropine (Aldrich, 706 mg, 5.0 mmol),
3,6-dichloropyridazine [Aldrich, 745 mg, 5.0 mmol) and potassium
t-butoxide (Aldrich, 1.12 g, 10 mmol) in THF (anhydrous, Aldrich,
25 mL) was stirred at 60.degree. C. under an atmosphere of nitrogen
for 16 hours. The mixture was concentrated under reduced pressure
and the residue purified by chromatography (150 g SiO.sub.2,
EtOAc:MeOH:NH3.H.sub.2O, 90:10:1, R.sub.f. 0.20) to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.03-2.36
(m, 8H), 2.45 (s, 3H), 3.38 [s (br.), 2H], 5.40 (t, J=5.09 Hz, 1H),
7.20 (d, J=9.16 Hz, 1H), 7.66 (d, J=9.16 Hz, 1H) ppm; MS
(DCI/NH.sub.3) m/z 254 (M+H).sup.+.
Example 1B
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole trifluoroacetate
[0168] The mixture of Example 1A (112 mg, 0.44 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole
(Aldrich, 232 mg, 0.954 mmol), bis(triphenylphosphine)palladium(II)
chloride (Aldrich, 7.02 mg, 0.01 mmol) and
biphenyl-2-yl-dicyclohexyl-phosphane (Strem Chemicals, 10.5 mg,
0.03 mmol) in dioxane/EtOH/Na.sub.2CO.sub.3 (aq., 1 M) (v. 1/1/1, 3
mL) were heated and microwaved to 150.degree. C. and 300 watts for
15 minutes in an Emry.TM. Creatror microwave. The solid was
filtered off with a syringe filter and the organic solution was
directly purified by preparative HPLC (Gilson, column, Xterra.RTM.
5:m, 40.times.100 mm. Eluting Solvent, MeCN/H.sub.20 containing
0.1% v. TFA (90% to 10% over 25 minutes, Flow rate of 40 mL/minute,
uv detector set to 254 nm). The fractions containing the desired
product were collected and concentrated under reduced pressure and
the residue was stirred in etherlethanol (v. 10/1, 5 mL) at ambient
temperature for 16 hours to provide the title compound. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 2.31-2.60 (m, 8H), 2.85 (s, 3H), 3.97
[s (br.), 2H], 5.53-5.62 (m, 1H), 6.56 (d, J=3.05 Hz, 1H),
7.24-7.34 (m, 2H), 7.51 (d, J=8.48 Hz, 1H), 7.74 (dd, J=8.65, 1.86
Hz, 1H), 8.09-8.17 (m, 2H) ppm; MS (DCI/NH.sub.3) m/z 335
(M+H).sup.+. Anal. Calculated for C.sub.20H.sub.22N.sub.4O.1.05
CF.sub.3CO.sub.2H.0.50 C.sub.2H.sub.5OH: C, 58.14; H, 5.50; N,
11.74. Found: C, 58.07; H, 5.44; N, 11.75.
Example 2
[0169]
(endo)-3-(6-Benzo[b]thiophen-5-yl-pyridazin-3-yloxy)-8-methyl-8-aza-
-bicyclo[3.2.1]octane trifluoroacetate
[0170] The product from Example 1A (121 mg, 0.48 mmol) and
2-benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Maybridge, 219 mg, 0.84 mmol) were treated according to the
procedure outlined in Example 1B to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.33-2.58 (m, 8H), 2.86
(s, 3H), 3.94-4.02 (m, 2H), 5.57-5.64 (m, 1H), 7.34 (d, J=9.15 Hz,
1H), 7.50 (d, J=5.42 Hz, 1H), 7.67 (d, J=5.42 Hz, 1H), 7.98 (dd,
J=8.48, 1.70 Hz, 1H), 8.06 (d, J=8.48 Hz, 1H), 8.20 (d, J=9.15 Hz,
1H), 8.44 (d, J=1.36 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 352
(M+H).sup.+. Anal. Calculated for C.sub.20H.sub.21N.sub.3OS.1.10
CF.sub.3CO.sub.2H: C, 55.91; H, 4.67; N, 8.81. Found: C, 55.90; H,
4.41; N, 8.59.
Example 3
[0171]
(endo)-3-[6-(Benzofuran-5-yl)-pyridazin-3-yloxy]-8-methyl-8-aza-bic-
yclo[3.2.1]octane trifluoroacetate
[0172] The product from Example 1A (131 mg, 0.52 mmol) and
1-benzofuran-5-ylboronic acid (Apollo, 166 mg, 1.02 mol) were
treated according to the procedure outlined in Example 1B to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.33-2.64 (m, 8H), 2.86 (s, 3H), 3.94-4.02 (m, 2H),
5.56-5.63 (m, 1H), 6.96 (d, J=1.36 Hz, 1H), 7.32 (d, J=9.16 Hz,
1H), 7.65 (d, J=8.82 Hz, 1H), 7.84 (d, J=2.37 Hz, 1H), 7.93 (dd,
J=8.82, 2.03 Hz, 1H), 8.15 (d, J=9.49 Hz, 1H), 8.22 (d, J=1.36 Hz,
1H) ppm; MS (DCI/NH.sub.3): m/z 336 (M+H).sup.+. Anal. Calculated
for C.sub.20H.sub.21N.sub.3O.sub.21.1 CF.sub.3CO.sub.2H: C, 57.86;
H, 4.83; N, 9.12. Found: C, 58.10; H, 4.54; N, 9.06.
Example 4
6-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indole trifluoroacetate
[0173] The product of Example 1A (158 mg, 0.62 mmol) was coupled
with indole-6-boronic acid (Frontier, 162 mg, 1.01 mol) were
treated according to the procedure outlined in Example 1B to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.33-2.59 (m, 8H), 2.85 (s, 3H), 3.93-4.01 (m, 2H), 5.58
(t, J=3.05 Hz, 1H), 6.51 (d, J=3.05 Hz, 1H), 7.29 (d, J=9.16 Hz,
1H), 7.35 (d, J=3.05 Hz, 1H), 7.58-7.64 (m, 1H), 7.66-7.73 (m, 1H),
8.01 (s, 1H), 8.13 (d, J=9.49 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z
335 (M+H).sup.+Anal. Calculated for C.sub.20H.sub.21N.sub.4O.1.10
CF.sub.3CO.sub.2H: C, 57.99; H, 5.06; N, 12.18. Found: C, 58.09; H,
4.95; N, 11.97.
Example 5
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indazole fumarate
Example 5A
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
[0174] A flask containing 5-bromo-1H-indazole (Ref. US 200319951 1,
9.45 g, 48 mmol) and bis(pinacolato)diboron (Aldrich, 15.5 g, 61
mmol) in dry DMF (160 mL) was added
[0175] KOAc (16.7 g, 170 mmol). The mixture was degassed and purged
with N.sub.2 three times followed by the addition of
PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 (Aldrich, 985 mg, 1.21 mmol).
The mixture was heated to 90.degree. C. and stirred for 24 hours.
The mixture was cooled to ambient temperature, diluted with ethyl
acetate (250 mL), washed with water (2.times.50 mL). The organic
phase was concentrated under reduced pressure and the residue was
purified by chromatography (400 g SiO.sub.2, hexane:EtOAc 90:10,
R.sub.f=0.6) to provide the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.36 (s, 12H), 7.51 (dt, J=8.48, 1.02 Hz, 1H),
7.73 (dd, J=8.48, 1.02 Hz, 1H), 8.08 (d, J=1.02 Hz, 1H), 8.23 (t,
J=1.02 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 245 (M+H).sup.+.
Example 5B
5-{-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-i-
ndazole
[0176] A mixture of Example 1A (158 mg, 0.62 mmol) and the product
of Example 5A (308 mg, 1.26 mol) were treated with
bis(triphenylphosphine)palladium(II) chloride (Aldrich, 7.02 mg,
0.01 mmol) and biphenyl-2-yl-dicyclohexyl-phosphane (Strem
Chemicals, 10.5 mg, 0.03 mmol) in dioxane/EtOH/Na.sub.2CO.sub.3
(aq., 1 M) (v. 1/1/1, 3 mL) were heated and microwaved to
150.degree. C. and 300 watts for 15 minutes in an Emry.TM. Creator
microwave reactor. The mixture was cooled to ambient temperature,
solid was filtered off with a syringe filter and the organic
solution was directly purified by chromatography (40 g SiO.sub.2,
EtOAc:MeOH:NH.sub.3H.sub.2O, 90:10:1, R.sub.f=0.10) to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.02-2.33
(m, 8H), 2.36 (s, 3H), 3.25 [s (br.), 2H], 5.47 (t, J=4.92 Hz, 1H),
7.23 (d, J=9.16 Hz, 1H), 7.67 (dt, J=8.82, 0.85 Hz, 1H), 8.07 (dd,
J=8.82, 1.70 Hz, 1H), 8.10-8.19 (m, 2H), 8.36 (dd, J=1.53, 0.85 Hz,
1H) ppm; MS (DCI/NH.sub.3): m/z 336 (M+H).sup.+.
Example 5C
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H--
indazole fumarate
[0177] The product of Example 5B (128 mg, 0.38 mmol) was treated
with fumaric acid (46 mg, 0.40 mmol) in EtOAc/EtOH (v. 1:1, 5 mL)
at ambient temperature for 15 hours. The mixture was filtered to
provide the titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD) 6
2.29-2.61 (m, 8H), 2.86 (s, 3H), 3.90-3.99 (m, 2H), 5.59 (t, J=4.92
Hz, 1H), 6.69 (s, 2H), 7.32 (d, J=9.16 Hz, 1H), 7.68 (d, J=8.82 Hz,
1H), 8.08 (dd, J=8.82, 1.70 Hz, 1H), 8.15-8.21 (m, 2H), 8.38 (dd,
J=1.70, 0.68 Hz, 1H) ppm; MS (DCI/NH3): m/z 336 (M+H).sup.+. Anal.
Calcd. for C.sub.19H.sub.21N.sub.5O.1.20 C.sub.4H.sub.4O.sub.4: C,
60.22; H, 5.48; N, 14.75. Found: C, 60.03; H, 5.17; N, 14.85.
Example 6
1-Methyl-5-{6-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin--
3-yl}-1H-indole trifluoroacetate
[0178] The product of Example 1A (121 mg, 0.48 mmol) and
N-methylindole-5-boronic acid (Frontier, 175 mg, 1 .O mol) were
treated according to the procedure outlined in Example 1B to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.22-2.70 (m, 8H), 2.86 (s, 3H), 3.93-4.03 (m, 2H),
5.53-5.62 (m, 1H), 6.57 (d, J=3.05 Hz, 1H), 7.26 (d, J=3.39 Hz,
1H), 7.37 (d, J=9.49 Hz, 1H), 7.54 (d, J=8.82 Hz, 1H), 7.80 (dd,
J=8.65, 1.87 Hz, 1H), 8.16 (d, J=1.70 Hz, 1H), 8.21 (d, J=9.16 Hz,
1H) ppm; MS (DCI/NH.sub.3): m/z 349 (M+H).sup.+. Anal. Calculated
for C.sub.21H.sub.24N.sub.4O.1.60 CF.sub.3CO.sub.2H: C, 54.75; H,
4.86; N, 10.55. Found: C, 54.69; H, 4.80; N, 10.58.
Example 7
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2-t-
rifluoromethyl-1H-indole trifluoroacetate
Example 7A
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluorormethhl-1H-ind-
ole
[0179] A mixture of 5-Bromo-2-trifluoromethyl-1H-indole (Ref. US
2005043347, 6.05 g, 22.9 mmol), bis(pinacolato)diboron (7.74 g,
30.5 mmol), KOAc (8.05 g, 82 mmol) and PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 (901 mg, 1.1 mmol) in anhydrous DMF (242 mL) were
processed according to the procedure of outlined in Example 5A to
provide the titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.36 (s, 12H), 6.91 (s, 1H), 7.43 (d, J=8.48 Hz, 1H), 7.64
(d, J=8.14 Hz, 1H), 8.11 (s, 1H) ppm; MS (DCI/NH.sub.3): 312
(M+H).sup.+.
Example 7B
(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl-4-nitro-benzoate
[0180] To a mixture of (endo)-tropine (2.82 g, 20.0 mmol),
4-nitrobenzoic acid (3.34 g, 20.0 mmol) and triphenylphosphine
(5.24 g, 20.0 mmol) in dry THF (100 mL) at room temperature was
added diisopropyl azodicarboxylate (4.04 g, 20.0 mmol) and the
resulting mixture stirred for 40 hours. The mixture was
concentrated under reduced pressure and the residue purified by
chromatography (140 g SiO.sub.2, EtOAc:MeOH:NH.sub.3H.sub.2O,
90:10:1, R.sub.f=0.30) to provide the titled compound. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.74-2.23 (m, 8H), 2.38 (s, 3H),
3.32-3.38 (m, 2H), 5.23-5.38 (m, 1H), 8.21 (d, J=8.82 Hz, 2H), 8.32
(d, J=8.82 Hz, 2H) ppm; MS (DCI/NH.sub.3): 291 (M+H).sup.+.
Example 7C
(exo)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol
[0181] The product of Example 7B (5.0 g, 0.017 mol) in ethanol (10
mL) was treated with NaOH (IN, 200 mL) at room temperature for 40
hours. The mixture was extracted with the mixture of 10%
isopropanol in chloroform (3.times.100 mL) and the combined
extracts concentrated under reduced pressure to provide the title
compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.55-1.69 (m,
4H), 1.80 (m, 2H), 1.99-2.09 (m, 2H), 2.28 (s, 3H), 3.14-3.21 (m,
2H), 3.79-3.93 (m, 1H) ppm. MS (DCI/NH.sub.3): 142 (M+H).sup.+.
Example 7D
(exo)-3-(6-chloro-pyridazin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0182] The product of Example 7D (721 mg, 5.1 mmol) and
3,6-dichlropyridazine (1.04 g, 7.0 mmol) were treated according to
the procedure outlined in Example 1A to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.87-2.07 (m, 4H),
2.23-2.31 (m, 2H), 2.37 (m, 2H), 3.60-3.69 (m, 2H), 5.54 (m, 1H),
7.15 (d, J=9.16 Hz, 1H), 7.64 (d, J=9.16 Hz, 1H) ppm; MS
(DCI/NH.sub.3): 254 (M+H).sup.+.
Example 7E
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2-t-
rifluoromethyl-1H-indole trifluoroacetate
[0183] The product of Example 7D (128 mg, 0.5 mmol) and the product
of Example 7A (311 mg, 1.0 mmol) were treated according to the
procedure outlined in Example 1B to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.01-2.73 (m, 8H), 2.85
(s, 3H), 4.01-4.10 (m, 2H), 5.64-5.80 (m, 1H), 7.02 (s, 1H), 7.23
(d, J=9.15 Hz, 1H), 7.60 (d, J=8.48 Hz, 1H), 7.95 (dd, J=8.48, 1.70
Hz, 1H), 8.13 (d, J=9.49 Hz, 1H), 8.26 (d, J=1.02 Hz, 1H) ppm; MS
(DCI/NH.sub.3): m/z 403 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.21F.sub.3N.sub.4O.1.55 CF.sub.3CO.sub.2H: C, 49.98;
H, 3.92; N, 9.67. Found: C, 49.93; H, 4.09; N, 9.69.
Example 8
5-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-i-
ndole fumarate
[0184] The product of Example 7D (154 mg, 0.61 mmol) and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-IH-indol (Aldrich,
243 mg, 1.0 mmol) were treated with
bis(triphenylphosphine)palladium(II) chloride (Aldrich, 7.02 mg,
0.01 mmol) and biphenyl-2-yl-dicyclohexyl-phosphane (Strem
Chemicals, 10.5 mg, 0.03 mmol) in dioxane/EtOH/aqeous 1M
Na.sub.2CO.sub.3 (v. 1/1/1.3 mL) were heated and microwaved to
150.degree. C. and 300 watts for 15 minutes in an Emry.TM. Creatror
microwave. The mixture was cooled to ambient temperature, the solid
was filtered off with a syringe filter and the organic solution was
directly purified by preparative HPLC (Gilson, Xterra.RTM. column,
7 .mu.m, 40.times.100 mm, eluting solvent, MeCN/H.sub.2O (with 0.1
M NH.sub.4HCO.sub.3/NH.sub.4OH, PH=10) (v. 90/10 to 10/90 over 25
minutes), flow rate, 40 mL/min., uv, 254 nm) to provide the free
base of the titled compound. The free base was treated with fumaric
acid (65 mg, 0.57 mmol) according to the procedure of Example 5C to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.04-2.50 (m, 6H), 2.57-2.69 (m, 2H), 2.85 (s, 3H),
3.99-4.05 (m, 2H), 5.63-5.78 (m, 1H), 6.56 (d, J=3.05 Hz, 1H), 6.69
(s, 2H), 7.20 (d, J=9.15 Hz, 1H), 7.31 (d, J=3.39 Hz, 1H), 7.51 (d,
J=8.48 Hz, 1H), 7.74 (dd, J=8.48, 1.70 Hz, 1H), 8.09 (d, J=9.49 Hz,
1H), 8.14 (d, J=1.02 Hz, 1H) ppm; MS (DCI/NH.sub.3): m/z 335
(M+H).sup.+; Anal. Calculated for C.sub.20H.sub.22N.sub.4O.1.20
C.sub.4H.sub.4O.sub.4: C, 62.88; H, 5.70; N, 11.83. Found: C,
62.63; H, 5.70; N, 11.96.
Example 9
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole bistosylate
Example 9A
(endo)-3-(6-Chloro-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0185] The mixture of (endo)-tropine (Aldrich, 2.82 g, 20 mmol),
2-chloro-5-iodopyridine (Aldrich, 2.39 g, 24 mmol), CuI (Strem
Chemicals, 0.19 g, 1 mmol) and 1,10-phenanthroline (Aldrich, 0.36
g, 2 mmol), Cs.sub.2CO.sub.3 (Aldrich, 6.52 g, 20 mmol) in toluene
(anhydrous, Aldrich, 25 mL) was stirred at 110.degree. C. for 40
hours. The mixture allowed to cool to ambient temperature and was
diluted with CH.sub.2Cl.sub.2 (100 mL) and washed with water
(2.times.10 mL). The organic solution was concentrated and the
title compound was purified by chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH:NH.sub.3.H.sub.2O, 90:10:1, R.sub.f. 0.10) to
provide the titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.97-2.08 (d, J=14.5 Hz, 2H), 2.13-2.18 (d, J=2.37 Hz, 2H),
2.45 (s, 3H), 3.35-3.41 (m, 2H), 4.66 (t, J=4.8 Hz, 1H), 7.35-7.42
(m, 2H), 7.96-8.04 (dd, J=2.3, 1.0 Hz, 1H) ppm. MS (DCI/NH.sub.3)
m/z 255 (M+H).sup.+, 253 (M+H).sup.+.
Example 9B
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole
[0186] The mixture of the product from Example 9A (150 mg, 0.59
mmol), 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol),
Pd(PPh.sub.3).sub.4 (Aldrich, 6.8 mg, 0.006 mmol) and
K.sub.2CO.sub.3 (2 M, 1 mL) was heated to 85.degree. C. in dioxane
(4 mL) for 12 hours. The mixture was cooled to ambient, filtered
and purified by preparative HPLC [Waters XTerra RP18 column,
30.times.100 mm, eluting solvents, MeCN/H.sub.2O (0.1 M aqueous
ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)
(v. 90/10 to 10/90 over 20 min.), flow rate 40 mL/min, uv, 250 nm]
to provide the titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta.1.94-2.06 (m, 2H), 2.06-2.27 (m, 6H), 2.34 (s, 3H), 3.21 [s
(br.), 2H], 4.67 (t, J=4.75 Hz, 1H), 6.52 (dd, J=3.05, 1.00 Hz,
1H), 7.26 (d, J=3.39 Hz, 1H), 7.40 (dd, J=8.82, 3.05 Hz, 1H), 7.45
(dt, J=8.48, 0.7 Hz, 1H), 7.63 (dd, J=8.65, 1.87 Hz, 1H), 7.77 (dd,
J=8.82, 0.70 Hz, 1H), 7.99-8.08 (m, 1 H), 8.18 (d, J=3.05 Hz, 1H)
ppm. MS (DCI/NH.sub.3) m/z 334 (M+H).sup.+.
Example 9C
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-in-
dole bistosylate
[0187] The product of Example 9B (40 mg, 0.12 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH H.sub.2O (Aldrich, 38
mg, 0.2 mmol) in a mixture of 25% isopropanol in iso-propylacetate
(5 mL) at ambient temperature for 10 hours. The mixture was
filtered to provide the titled compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 2.25-2.56 (m, 13H), 2.77-2.89 (m, 4H),
3.87-4.03 (m, 2H), 4.90-2.04 (m, 1H), 6.66 (dd, J=3.1, 0.7 Hz, 1H),
7.19 (d, J=8.10 Hz, 4H), 7.43 (d, J=3.39 Hz, 1H), 7.55-7.65 (m,
2H), 7.68 (d, J=8.14 Hz, 4H), 8.10-8.17 (m, 1H), 8.22-8.38 (m, 2H),
8.46 (d, J=2.03 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 334
(M+H).sup.+. Anal. Calculated for C.sub.21H.sub.23N.sub.3O 2.05
C.sub.7H.sub.8SO.sub.3.2.00H.sub.2O: C, 57.52; H, 6.17; N, 5.72.
Found: C, 57.88; H, 5.99; N, 5.33.
Example 10
(endo)-3-(6-Benzo[b]thiophen-5-yl-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[-
3.2.1]octane bistosylate
Example 10A
2-Benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
[0188] A mixture of 5-bromo-benzo[b]thiophene (Maybridge, 4.26 g,
0.0200 mol), bis(pinacolato)diboron (Aldrich, 6.09 g, 0.0240 mol)
and potassium acetate (Aldrich, 2.94 g, 0.0300 mol) in 1,4-dioxane
(Aldrich, 50 mL) was degassed and purged with N.sub.2 three times.
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
PdCl.sub.2 (dppf) CH.sub.2Cl.sub.2 (300 mg, 0.4 mmol, Aldrich) was
and the solution was heated to 100.degree. C. for 20 hours. The
mixture was then cooled to room temperature, diluted with 300 mL of
EtOAc and washed with brine (2.times.20 mL). The organic solution
was concentrated under reduced pressure and the residue was
chromatographed to provide the title product. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.36-1.41 (S, 12H), 7.35 (d, J=5.50 Hz, 1H),
7.42 (d, J=5.70 Hz, 1H), 7.75 (d, J=8.14 Hz, 1H), 7.89 (d, J=8.14
Hz, 1H), 8.31 (s, 1H) ppm. MS (DCI/NH.sub.3) m/z 278
(M+H).sup.+.
Example 10B
(endo)-3-(6-Benzo[b]thiophen-5-yl-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[-
3.2.1]octane
[0189] The product from Example 9A (150 mg, 0.59 mmol) and the
product of 10A (231.6 mg, 0.89 mmol) was treated with
Pd(PPh.sub.3).sub.4 (Aldrich, 6.8 mg, 0.006 mmol) according to the
procedure of outlined in Example 9B. The title product was purified
by preparative HPLC [Waters XTerra RP18 column, 30.times.100 mm,
eluting solvents, MeCN/H.sub.2O (0.1 M aqueous ammonium
bicarbonate, adjusted to pH 10 with ammonium hydroxide) (v. 90/10
to 10/90 over 20 min.), flow rate 40 mL/min, uv, 250 nm]. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. 1.93-2.07 (m, 2H), 2.06-2.28 (m,
6H), 2.34 (s, 3H), 3.21 [s (br.), 2H], 4.70 (t, J=5.26 Hz, 1H),
7.37-7.50 (m, 2H), 7.61 (d, J=5.43 Hz, 1H), 7.80-7.92 (m, 2H),
7.94-8.02 (m, 1H), 8.25 (d, J=2.71 Hz, 1H), 8.34 (d, J=1.36 Hz, 1H)
ppm. MS (DCI/NH.sub.3) m/z 351 (M+H).sup.+.
Example 10C
(endo)-3-(6-Benzo[b]thiophen-5-yl-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[-
3.2.1]octane bistosylate
[0190] The product of Example 10B (70 mg, 0.20 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH H.sub.2O (Aldrich, 38
mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate
as outlined in Exampled 9C. The mixture was filtered to provide the
titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.35 (s,
6H), 2.48-2.62 (m, 8H), 2.78 (s, 3H), 3.88-4.05 (m, 2H), 5.02 (t,
J=4.58 Hz, 1H), 7.22 (d, J=7.80 Hz, 4H), 7.55 (d, J=5.76 Hz, 1H),
7.70 (d, J=8.48 Hz, 4H), 7.75-7.84 (m, 2H), 8.12-8.22 (m, 2H), 8.29
(d, J=9.20 Hz, 1H) 8.37 (d, J=1.70 Hz, 1H), 8.56 (d, J=3.05 Hz, 1H)
ppm. MS (DCI/NH.sub.3): m/z 351 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.23N.sub.2OS 2.00 C.sub.7H.sub.8SO.sub.3.1.00H.sub.2O:
C, 58.97; H, 5.66; N, 3.93. Found: C, 58.86; H, 5.61; N, 5.71.
Example 11
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-ind-
ole tosylate
Example 11A
[0191]
(exo)-3-(6-Chloro-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]oct-
ane tosylate To the mixture of (endo)-tropine (Aldrich, 2.82 g, 20
mmol), 2-chloro-5-hydroxypyridine (Aldrich, 1.29 g, 10 mmol) and
Ph.sub.3P (Aldrich, 5.24 g, 20 mmol) was added diisopropyl
azadicarboxylate (Aldrich, 4.04 g, 20 mmol) in THF (anhydrous,
Aldrich, 100 mL) and the mixture was stirred for two days. The
mixture was concentrated under reduced pressure and the title
product was purified by chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH:NH.sub.3.H.sub.2O, 90:10:1, R.sub.f. 0.40) as
solid (1.98 g, yield, 78.3%). .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.63-1.92 (m, 4H), 1.97-2.20 (m, 4H), 2.33 (s, 3H), 3.34
(s, 2H), 4.51-4.75 (m, 1H), 7.27-7.37 (dd, J=8.80, 0.7 Hz, 1H),
7.37-7.49 (dd, J=8.80, 3.00 Hz, 1H), 8.01 (d, J=3.05 Hz, 1H) ppm.
MS (DCI/NH.sub.3) m/z 255 (M+H).sup.+, 253 (M+H).sup.+.
Example 11B
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxyl]-pyridin-2-yl}-1H-in-
dole
[0192] The mixture of the product from Example 11A (150 mg, 0.59
mmol), 5-Indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol) and
Pd(PPh.sub.3).sub.4 (Aldrich, 6.8 mg, 0.006 mmol) and
K.sub.2CO.sub.3 (2 M, 1 mL) in dioxane (4 mL) was stirred at
85.degree. C. for 12 hours according to the procedure of outlined
in Example 9B. The title product was purified by preparative HPLC
[Waters XTerra RP18 column, 30.times.100 mm, eluting solvents,
MeCN/H.sub.2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH
10 with ammonium hydroxide) (v. 90/10 to 10/90 over 20 min.), flow
rate 40 mL/min, uv, 250 nm]. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.61-1.97 (m, 4H), 2.00-2.23 (m, 4H), 2.35 (s, 3H),
3.22-3.38 (m, 2H), 4.56-4.78 (m, 1H), 6.51 (d; J=4.07 Hz, 1H), 7.26
(d, J=3.39 Hz, 1H), 7.40-7.52 (m, 2H), 7.62 (dd, J=8.48, 1.70 Hz,
1H), 7.75 (d, J=8.82 Hz, 1H), 8.03 (s, 1H), 8.21 (d, J=2.37 Hz, 1H)
ppm. MS (DCI/NH.sub.3) m/z 334 (M+H).sup.+.
Example 11C
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-ind-
ole tosylate
[0193] The product of Example 11B (50 mg, 0.15 mmol) was treated
with p-toluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 38
mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate
(5 mL) at ambient temperature for 10 hours according to the
procedure of Example 9C. The mixture was filtered to provide the
titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.90-2.13 (m, 2H), 2.17-2.31 (m, 2H), 2.33-2.42 (m, 5H), 2.44-2.58
(m, 2H), 2.83 (s, 3H), 4.02[s (br.), 2H], 4.86-5.03 (m, 1H), 6.53
(dd, J=3.22, 0.85 Hz, 1H), 7.22 (d, J=8.14 Hz, 1H), 7.26-7.32 (m,
1H), 7.47 (d, J=8.48 Hz, 1H), 7.56-7.66 (m, 2H), 7.70 (dt, J=8.10,
1.80 Hz, 2H), 7.82 (d, J=8.82 Hz, 1H), 8.05 (d, J=1.36 Hz, 1H),
8.28 (d, J=3.05 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 334
(M+H).sup.+. Anal. Calculated for C.sub.21H.sub.23N.sub.3O.1.00
C.sub.7H.sub.8SO.sub.3.1.00H.sub.2O: C, 64.22; H, 6.35; N, 8.02.
Found: C, 64.07; H, 6.16; N, 7.69.
Example 12
(exo)-3-[6-(Benzofuran-5-yl)-pyridin-3-yloxy]-8-methyl-8-aza-bicyclo[3.2.1-
]octane bistrifluoroacetate
[0194] The product of Example 11A (130 mg, 0.52 mmol) and
1-benzofuran-5-ylboronic acid (Maybridge, 166 mg, 1.0 mmol) were
treated according to the procedure outlined in Example 1B to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.98-2.58 (m, 8H), 2.84 (s, 3H), 3.98-4.09 (m, 2H),
4.93-5.07 (m, 1H), 6.94 (d, J=1.36 Hz, 1H), 7.62 (d, J=8.81 Hz,
1H), 7.73 (dd, J=8.81, 3.05 Hz, 1H), 7.80-7.86 (m, 2H), 7.92 (d,
J=8.48 Hz, 1H), 8.13 (d, J=1.36 Hz, 1H), 8.38 (d, J=2.37 Hz, 1H)
ppm; MS (DCI/NH.sub.3): m/z 335 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.22N.sub.2O.sub.22.00 CF.sub.3CO.sub.2H: C, 53.39; H,
4.30; N, 4.98. Found: C, 53.28; H, 4.04; N, 4.95.
Example 13
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[32.1]oct-3-yloxy]-pyridin-2-yl}-1H-inda-
zole hemifumarate
[0195] The product of Example 11A (139 mg, 0.55 mmol) and the
product of Example 5A (325 mg, 1.3 mmol) were treated according to
the procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.97-2.45 (m, 8H), 2.73
(s, 3H), 3.80-3.89 (m, 2H), 4.84-4.96 (m, 1H), 6.68 (s, 1H), 7.56
(dd, J=8.82, 3.05 Hz, 1H), 7.62 (d, J=8.82 Hz, 1H), 7.84 (d, J=8.82
Hz, 1H), 7.97 (dd, J=8.82, 1.70 Hz, 1H), 8.12 (d, J=1.02 Hz, 1H),
8.27 (dd, J=1.53, 0.85 Hz, 1H), 8.32 (d, J=3.05 Hz, 1H) ppm; MS
(DCI/NH.sub.3): m/z 335 (M+H).sup.+.
Example 14
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-2-trif-
luoromethyl-1H-indole fumarate
[0196] The product of Example 11A (130 mg, 0.52 mmol) and the
product of Example 7A (319 mg, 1.0 mmol) were treated according to
the procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.99-2.53 (m, 8H), 2.83
(s, 3H), 3.96-4.03 (m, 2H), 4.85-5.02 (m, 1H), 6.69 (s, 2H), 6.97
(s, 1H), 7.50-7.62 (m, 2H), 7.78-7.88 (m, 2H), 8.16 (d, J=1.36 Hz,
1H), 8.31 (d, J=2.71 Hz, 1H) ppm; MS (DCI/NH.sub.3): m/z 402
(M+H).sup.+. Anal. Calculated for
C.sub.22H.sub.22F.sub.3N.sub.3O.1.20 C.sub.4O.sub.4H.sub.4: C,
59.53; H, 5.00; N, 7.77. Found: C, 59.26; H, 5.06; N, 7.86.
Example 15
4-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-ind-
ole bistrifluoroacetate
[0197] The product of Example 11A (130 mg, 0.52 mmol) and
indole-4-boronic acid (Apollo, 165 mg, 1.0 mmol) were treated
according to the procedure outlined in Example 1B to provide the
title compound. 1H NMR (300 MHz, CD.sub.3OD) .delta. 2.03-2.64 (m,
8H), 2.85 (s, 3H), 4.00-4.10 (m, 2H), 5.02-5.16 (m, 1H), 6.70 (d,
J=2.37 Hz, 1H), 7.25-7.40 (m, 2H), 7.44 (d, J=3.05 Hz, 1H), 7.59
(d, J=7.80 Hz, 1H), 8.01-8.17 (m, 2H), 8.50 (d, J=2.71 Hz, 1H) ppm;
MS (DCI/NH.sub.3): m/z 334 (M+H).sup.+; Anal. Calculated for
C.sub.21H.sub.23N.sub.3O.2.00 C.sub.2F.sub.3O.sub.2H: C, 53.48; H,
4.49; N, 7.48. Found: C, 53.29; H, 4.17; N, 7.35.
Example 16
4-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-phenyl-
amine bistrifluoroacetate
Example 16A
4-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-phenyl-
amine
[0198] The product of Example 11A (379 mg, 1.5 mmol) and
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine
(Aldrich, 552 mg, 2.5 mmol) were processed according to the
procedure of Example 5B. The mixture was purified by chromatography
(140 g SiO.sub.2, EtOAc:MeOH:NH.sub.3H.sub.2O, 90:10:1) to provide
the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.76-1.91 (m, 4H), 2.08-2.21 (m, 4H), 3.35-3.42 [s (br.), 2H],
4.62-4.76 (m, 1H), 6.73-6.81 (m, 2H), 7.42 (dd, J=8.81, 3.05 Hz,
1H), 7.57-7.68 (m, 3H), 8.15 (d, J=2.37 Hz, 1H) ppm; MS
(DCI/NH.sub.3): m/z 310 (M+H).sup.+.
Example 16B
4-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-phenyl-
amine bistrifluoroacetate
[0199] The product of Example 16A (135 mg, 0.44 mmol) was
repurified by preparative HPLC (Gilson, Xterra.RTM. column, 5
.mu.m, 40.times.100 mm. Eluting Solvent, MeCN/H.sub.2O (with 0.1%
v. TFA) (v. 90/10 to 10/90 over 25 min.) Flow rate, 40 mL/min., uv,
254 nm). The fractions of the desired product were collected and
concentrated under reduced pressure and the residue was stirred in
Ether/Ethanol (v. 10/1, 5 mL) at room temperature for 16 hours. The
mixture was filtered to provide the bis trifluoroacetate salt.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.99-2.56 (m, 8H), 4.03
[s (br.), 2H], 4.93-5.07 (m, 1H), 6.96-7.07 (m, 2H), 7.73-7.86 (m,
3H), 7.88-7.98 (m, 1H), 8.32 (d, J=3.05 Hz, 1H) ppm; MS
(DCI/NH.sub.3) m/z 310 (M+H).sup.+; Anal. Calculated for
C.sub.19H.sub.23N.sub.3O.2.30 CF.sub.3CO.sub.2H: C, 49.58; H, 4.46;
N, 7.53. Found: C, 49.58; H, 4.36; N, 7.44.
Example 17
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole tosylate
Example 17A
(endo)-3-(5-Bromo-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0200] (endo)-Tropine (Aldrich, 282 mg, 2 mmol) was treated with
.sup.tBuOK (Aldrich, 224 mg, 2 mmol) in THF (20 mL) at ambient
temperature for 1 hour followed by the addition of
3,6-dibromopyridine (Aldrich, 569 mg, 2.4 mmol). The mixture was
stirred at 60.degree. C. for additional 10 hours and then
concentrated under reduced pressure. The residue was dissolved in
CHCl.sub.3/isopropanol (10:1, 50 mL) and washed with brine
(2.times.5 mL). The organic solution was concentrated under reduced
pressure and the title compound was purified by chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.3H.sub.2O, 90:10:1,
R.sub.f. 0.10). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.93 (d,
J=14.50 Hz, 2H), 2.02-2.23 (m, 6H), 2.31 (s, 3H), 3.17 [s (br.),
2H], 5.16 (t, J=5.26 Hz, 1H), 6.70 (d, J=8.82 Hz, 1H), 7.77 (dd,
J=8.81, 2.71 Hz, 1H), 8.16 (d, J=2.71 Hz, 1H) ppm. MS
(DCI/NH.sub.3): 299 (M+H).sup.+, 297 (M+H).sup.+.
Example 17B
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole
[0201] The mixture of the product from Example 17A (150 mg, 0.50
mmol), 5-indolylboronic acid (Rsycor, 121.9 mg, 0.75 mmol),
Pd(PPh3).sub.4 (Aldrich, 6.8 mg, 0.006 mmol) and K2C03 (2 M, 1 mL)
in dioxane (4 mL) was stirred at 85.degree. C. for 12 hours
according to the procedure of outlined in Example 9B. The title
product was purified by preparative HPLC [Waters XTerra RP18
column, 30.times.100 mm, eluting solvents, MeCN/H.sub.2O (0.1 M
aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium
hydroxide) (v. 90/10 to 10/90 over 20 min.), flow rate 40 mL/min,
uv, 250 nm]. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.01 (d,
J=14.30 Hz, 2H), 2.06-2.28 (m, 6H), 2.34 (s, 3H), 3.17-3.26 (m,
2H), 5.19 (t, J=5.26 Hz, 1H), 6.49 (d, J=2.37 Hz, 1H), 6.82 (d,
J=8.48 Hz, 1H), 7.26 (d, J=3.05 Hz, 1H), 7.31 (dd, J=8.48, 1.70 Hz,
1H), 7.45 (d, J=8.48 Hz, 1H), 7.73 (s, 1H), 7.96 (dd, J=8.65, 2.54
Hz, 1H), 8.35 (d, J=2.03 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 334
(M+H).sup.+.
Example 17C
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-in-
dole bistosylate
[0202] The product of Example 11B (40 mg, 0.15 mmol) was treated
with p-toluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 38
mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate
(5 mL) at ambient temperature for 10 hours according to the
procedure outlined in Example 9C. The mixture was filtered to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.32-2.58 (m, 14H), 2.81-2.88 (s, 3H), 3.89-4.01 (m, 2H),
5.27-5.41 (m, 1H), 6.52 (d, J=3.39 Hz, 1H), 7.13 (d, J=8.48 Hz,
1H), 7.23 (d, J=7.80 Hz, 4H), 7.35 (dd, J=8.48, 2.03 Hz, 1H), 7.49
(d, J=8.48 Hz, 1H), 7.70 (d, J=8.14 Hz, 4H), 7.79 (s, 1H), 8.24
(dd, J=8.65, 2.54 Hz, 1H), 8.47 (d, J=2.71 Hz, 1H) ppm. MS
(DCI/NH.sub.3): m/z 334 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.23N.sub.3O.2.20 C.sub.7H.sub.8SO.sub.3.2.00H.sub.2O:
C, 58.42; H, 6.01; N, 5.62. Found: C, 58.02; H, 5.84; N, 5.31.
Example 18
(endo)-3-(5-Benzo[b]thiophen-5-yl-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[-
3.2.1]octane tosylate
Example 18A
(endo)-3-(5-Benzo[b]thiophen-5-yl-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[-
3.2.1]octane
[0203] The mixture of Example 17A (150 mg, 0.50 mmol), the product
of Example 10A (197.0 mg, 0.75 mmol), Pd(PPh.sub.3).sub.4 (Aldrich,
6.8 mg, 0.006 mmol) and K.sub.2CO.sub.3 (2 M, 1 mL) in dioxane (4
mL) was processed according to the procedure outlined in Example
9B. The title product was purified by preparative HPLC [Waters
XTerra RP18 column, 30.times.100 mm, eluting solvents,
MeCN/H.sub.2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH
10 with ammonium hydroxide) (v. 90/10 to 10/90 over 20 min.), flow
rate 40 mL/min, uv, 250 nm]. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.99 (d, J=14.50 Hz, 1H), 2.03-2.28 (m, 6H), 2.33 (s, 3H),
3.14-3.25 (m, 2H), 5.23 (t, J=5.26 Hz, 1H), 6.86 (d, J=8.48 Hz,
1H), 7.43 (d, J=5.43 Hz, 1H), 7.57 (dd, J=8.48, 1.70 Hz, 1H), 7.61
(d, J=5.43 Hz, 1H), 7.91-8.09 (m, 3H), 8.42 (d, J=1.70 Hz, 1H) ppm.
MS (DCI/NH.sub.3) m/z 351 (M+H).sup.+.
Example 18B
(endo)-3-(5-Benzo[b]thiophen-5-yl-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[-
3.2.1]octane tosylate
[0204] The product of Example 18A (60 mg, 0.17 mmol) was treated
with p-toluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 38
mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate
(5 mL) at ambient temperature for 10 hours according to the
procedure outlined in Example 9C. The mixture was filtered to
provide the titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.34-2.45 (m, 9H), 2.48-2.55 (m, 2H), 2.84 (s, 3H),
3.88-4.00 (m, 2H), 5.39 (t, J=4.41 Hz, 1H), 7.06 (d, J=8.82 Hz,
1H), 7.23 (d, J=7.80 Hz, 2H), 7.45 (d, J=5.43 Hz, 1H), 7.59 (dd,
J=8.48, 1.70 Hz, 1H), 7.64 (d, J=5.76 Hz, 1H), 7.70 (d, J=8.48 Hz,
2H), 8.00 (d, J=8.48 Hz, 1H), 8.08 (d, J=1.36 Hz, 1H), 8.18 (dd,
J=8.82, 2.37 Hz, 1H), 8.51 (d, J=2.03 Hz, 1H) ppm. MS
(DCI/NH.sub.3): m/z 351 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.23N.sub.2OS.1.10 C.sub.7H.sub.8SO.sub.3.1.00H.sub.2O:
C, 61.79; H, 5.93; N, 5.02. Found: C, 61.44; H, 5.63; N, 4.68.
Example 19
5-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole fumarate
Example 19A
(exo)-3-(5-Bromo-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0205] The product of Example 7C (721 mg, 5.1 mmol) and
2,5-dibromopyridine (1.66 g, 7.0 mmol) were treated according to
the procedure outlined in Example 1A to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.88-2.47 (m, 8H), 2.74
(s, 3H), 3.82-3.90 (m, 2H), 5.34-5.48 (m, 1H), 6.71 (d, J=8.82 Hz,
1H), 7.78 (dd, J=8.82, 2.71 Hz, 1H), 8.20 (d, J=2.37 Hz, 1H) ppm;
MS (DCI/NH.sub.3): 2997 (M+H).sup.+, 297 (M+H).sup.+.
Example 19B
5-{6-[(exo]-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole fumarate
[0206] The product of Example 19A (129 mg, 0.434 mmol) and
5-indolylboronic acid (165 mg, 1.02 mmol) were treated according to
the procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.97-2.12 (m, 2H),
2.20-2.46 (m, 4H), 2.48-2.60 (m, 2H), 2.84 (s, 3H), 3.96-4.07 (m,
2H), 5.43-5.60 (m, 1H), 6.49 (d, J=3.05Hz, 1H), 6.70 (s, 2H), 6.82
(d, J=8.48 Hz, 1H), 7.23-7.35 (m, 2H), 7.46 (d, J=8.14 Hz, 1H),
7.73 (d, J=1.70 Hz, 1H), 7.95 (dd, J=8.65, 2.54 Hz, 1H), 8.37 (d,
J=2.03 Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 334 (M+H).sup.+; Anal.
Calculated for
C.sub.21H.sub.23N.sub.3O.1.10C.sub.4O.sub.4H.sub.4.1.00H.sub.2O: C,
63.67; H, 6.18; N, 8.77. Found: C, 63.77; H, 6.26; N, 8.64.
Example 20
[6-(1H-Indol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct--
3-yl]-amine bis(hydrochloride)
Example 20A
(6-Chloro-pyridin-3-yl)-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-ami-
ne
[0207] A mixture of tropinone (Aldrich, 2.78 g, 20 mmol),
6-chloro-pyridin-3-ylamine (Aldrich, 2.83 g, 22 mmol),
Na.sub.2SO.sub.4 (anhydrous, Aldrich, 21.3 g, 150 mmol) and
NaBH(OAc).sub.3 (Aldrich, 8.48 g, 40 mmol) in HOAc (50 mL) at
ambient temperature was stirred for 15 hours. The mixture was
filtered and the filtrate washed with EtOH (2.times.10 mL). The
organic solution was concentrated under reduced pressure and the
title compound obtained by purified using chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.3.H.sub.2O, 90:10:2,
R.sub.f. 0.10). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.16 (d,
J=15.26 Hz, 2H), 2.25-2.35 (m, 2H), 2.37-2.60 (m, 4H), 2.81 (s,
3H), 3.65 (t, J=5.93 Hz, 1H), 3.79-3.98 (m, J=2.71 Hz, 1H), 7.09
(dd, J=8.50, 3.00 Hz, 1H), 7.21 (d, J=8.80 Hz, 1H), 7.73 (d, J=2.71
Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 254 (M+H).sup.+, 252
(M+H).sup.+.
Example 20B
[6-(1H-Indol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct--
3-yl]-amine
[0208] The mixture of Example 20A (250 mg, 1.0 mmol),
5-indolylboronic acid (Rsycor, 241.0 mg, 1.50 mmol),
bis(triphenylphosphine)palladium(II) chloride (Aldrich, 10.0 mg,
0.01 mmol) and biphenyl-2-yl-dicyclohexyl-phosphane (Strem
Chemicals, 11.0 mg, 0.03 mmol) in dioxane/EtOH/1M aqueous
Na.sub.2CO.sub.3 (v. 1/1/1 3 mL) were heated and microwaved to
130.degree. C. and 300 watts for 15 minutes in an Emry.TM. Creator
microwave. The mixture was filtered through a syringe filter and
the liquid was purified by preparative HPLC [Waters XTerra RP18
column, 30.times.100 mm, eluting solvents, MeCN/H.sub.2O (0.1 M
aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium
hydroxide) (v. 90/10 to 10/90 over 20 min.), flow rate 40 mL/min,
uv, 250 nm] to provide the titled compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.88 (d, J=15.20 Hz, 2H) 2.05-2.18 (m, 4H),
2.18-2.31 (m, 2H), 2.37 (s, 3H), 3.26 [s (br.), 2H)], 3.60 (t,
J=6.44 Hz, 1H), 6.49 (d, J=3.05 Hz, 1H), 7.05 (dd, J=8.82, 2.71 Hz,
1H), 7.24 (d, J=3.05 Hz, 1H), 7.42 (d, J=8.48 Hz, 1H), 7.49-7.64
(m, 2H), 7.95 (s, 1 H) ppm. MS (DCI/NH.sub.3) m/z 333
(M+H).sup.+.
Example 20C
[6-(1H-Indol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct--
3-yl]-amine bis(hydrochloride)
[0209] The solution of Example 20B (160 mg, 0.48 mmol) in EtOAc
(10.0 mL) at ambient temperature was treated with 4M hydrochloric
acid in dioxane (0.5 mL, 2.0 mmol) for 10 hours. The title compound
was obtained by filtration. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.25 (d, J=15.65 Hz, 2H), 2.32-2.53 (m, 4H), 2.54-2.64 (m,
2H), 2.84 (s, 3H), 3.83 (t, J=6.14 Hz, 1H), 3.97 [s (br.), 2H],
6.63 (d, J=3.07 Hz, 1H), 7.40-7.41 (m, 1H), 7.54 (dd, J=8.60, 1.90
Hz, 1H), 7.62 (d, J=8.60 Hz, 1H), 7.83-7.95 (m, 2H), 8.06 (d,
J=1.53 Hz, 1H), 8.12 (d, J=8.90 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z
333 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.24N.sub.42.30HCl. 3.35H.sub.2O: C, 52.92; H, 6.98; N,
11.75. Found: C, 52.87; H, 6.78; N, 11.35.
Example 21
[6-(Benzofuran-5-yl)-pyridin-3-yl]-[(endo-8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl]-amine fumarate
[0210] The product of Example 20A (136 mg, 0.54 mmol) and
1-benzofuran-5-ylboronic acid (Aldrich, 185 mg, 1.14 mmol) were
treated according to the procedure outlined in Example 8 to provide
the title compound. NMR (300 MHz, CD.sub.3OD) .delta. 2.14-2.57 (m,
8H), 2.83 (s, 3H), 3.74 (t, J=5.93 Hz, 1H), 3.90 [s (br.), 2H],
6.69 (s, 2H), 6.89 (d, J=1.36 Hz, 1H), 7.13 (dd, J=8.65, 2.88 Hz,
1H), 7.54 (d, J=8.82 Hz, 1H), 7.68 (d, J=8.82 Hz, 1H), 7.72-7.79
(m, 2H), 7.99-8.07 (m, 2H) ppm; MS DCI/NH.sub.3): m/z 334
(M+H).sup.+.
Example 22
[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(2-trifluoromethyl-1H-in-
dol-5-yl)-pyridin-3-yl]-amine bistrifluoroacetate
[0211] The product of Example 20A (130 mg, 0.52 mmol) and the
product of Example 7A (262 mg, 0.84 mmol) were treated according to
the procedure outlined in Example 1B to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.17-2.62 (m, 8H), 2.84
(s, 3H), 3.82 (t, J=5.93 Hz, 1H), 3.96 [s (br.), 2 HI, 7.06 (s,
1H), 7.63-7.80 (m, 3H), 7.95 (d, J=2.71 Hz, 1H), 8.06 (d, J=9.16
Hz, 1H), 8.15 (d, J=1.36 Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 401
(M+H).sup.+; Anal. Calculated for
C.sub.22H.sub.22F.sub.3N.sub.3O.2.00 CF.sub.3CO.sub.2H. 0.70
NH.sub.4OH: C, 47.75; H, 4.24; N, 7.92. Found: C, 47.69; H, 3.91;
N, 8.14.
Example 23
[6-(1H-Indazol-5-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oc-
t-3-yl]-amine fumurate
[0212] The product of Example 20A (128 mg, 0.51 mmol) and the
product of Example 5A (205 mg, 0.84 mmol) were treated according to
the procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.11-2.55 (m, 8H), 2.79
(s, 3H), 3.73 (t, J=5.93 Hz, 1H), 3.85 [s (br.), 2H], 6.67 (s, 3H),
7.13 (dd, J=8.65, 2.88 Hz, 1H), 7.59 (d, J=8.82 Hz, 1H), 7.70 (d,
J=8.82 Hz, 1H), 7.90 (dd, J=8.82, 1.70 Hz, 1H), 8.04 (d, J=2.71 Hz,
1H), 8.09 (s, 1H), 8.18 (s, 1H) ppm; MS DCI/NH.sub.3): m/z 334
(M+H).sup.+; Anal. Calculated for C.sub.20H.sub.23N.sub.5 1.50
C.sub.4O.sub.4H.sub.4 1.00 NH.sub.4OH: C, 57.55; H, 6.32; N, 15.49.
Found: C, 57.46; H, 6.26; N, 15.55.
Example 24
[6-(1H-Indol-4-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct--
3-yl]-amine fumarate
[0213] The product of Example 20A (130 mg, 0.52 mmol) and
indole-4-boronic acid (Apollo, 165 mg, 1.0 mmol) were treated
according to the procedure outlined in Example 8 to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.16-2.60
(m, 8H), 2.84 (s, 3H), 3.76 (t, J=5.76 Hz, 1H), 3.88-3.95 [s (br.),
2 HI, 6.69 (s, 2H), 6.70 (d, J=3.39 Hz, 1H), 7.14-7.32 (m, 4H),
7.40 (d, J=7.80 Hz, 1H), 7.68 (d, J=8.48 Hz, 1H), 8.06 (d, J=2.71
Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 333 (M+H).sup.+; Anal.
Calculated for C.sub.21H.sub.24N.sub.4 1.40 C.sub.4O.sub.4H.sub.4
0.90H.sub.2O: C, 62.50; H, 6.19; N, 10.96. Found: C, 62.40; H,
6.17; N, 11.04.
Example 25
[(endo)-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(1H-indol-5-yl)-pyridin-3-yl]-ami-
ne
Example 25A
(endo)-3-(6-Chloro-pyridin-3-ylamino)-8-aza-bicyclo[3.2.1]octane]-8-carbox-
ylic acid tert-butyl ester
[0214] The mixture of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester (Fluka, 3.50 g, 15.50 mmol),
6-chloro-pyridin-3-ylamine (Aldrich, 2.20 g, 17.1 mmol),
Na.sub.2SO.sub.4 (anhydrous, Aldrich, 16.6 g, 116 mmol) and
NaBH(OAc).sub.3 (Aldrich, 6.59 g, 31.1 mmol) in HOAc (40 mL) was
stirred at ambient temperature for 15 hours according to the
procedure outlined in Example 20A. The title compound was purified
by chromatography (SiO.sub.2, hexane:EtOAc, 50:50, R.sub.f. 0.40).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.41-1.56 (m, 9H),
1.58-2.90 (m, 8H) 4.13-4.33 (m, 1H), 4.37-4.54 (m, 2H), 7.00 (dd,
J=8.81, 3.05 Hz, 0.5H), 7.15 (d, J=8.14 Hz, 0.5H), 7.26 (dd,
J=8.30, 3.10 Hz, 0.5H) 7.41 (d, J=8.48 Hz, 0.5H), 7.68 (d, J=3.05
Hz, 0.5H) 7.84 (d, J=2.37 Hz, 0.5H) ppm. MS (DCI/NH.sub.3) m/z 340
(M+H).sup.+, 338 (M+H).sup.+.
Example 25B
[(endo)-8-Aza-bicyclo[3.2.1]oct-3-yl]-(6-chloro-pyridin-3-yl)-amine
[0215] The product of Example 25A (2.92 g, 8.7 mmol) was treated
with trifluoroacetic acid (5 mL) in dichloromethane (20 mL) at
ambient temperature for 4 hours. The mixture was concentrated under
reduced pressure and the residue purified by chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.3.H.sub.2O, 90:10:2,
R.sub.f. 0.10) to provide the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.71-1.94 (m, 4H) 2.03-2.22 (m, 4H), 3.42-3.64
(m, 3H), 6.98 (dd, J=8.82, 3.05 Hz, 1H), 7.14 (d, J=8.14 Hz, 1H),
7.65 (d, J=3.05 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 238 (M+H)+, 240
(M+H).sup.+.
Example 25C
[(endo)-8-aza-bicyclo[3.2.1]oct-3-yl]-[6-(1H-indol-5-yl)-pyridin-3-yl]-ami-
ne
[0216] The product of Example 20A (250 mg, 1.0 mmol),
5-indolylboronic acid (Rsycor, 241.0 mg, 1.50 mmol),
bis(triphenylphosphine)palladium(II) chloride (Aldrich, 10.0 mg,
0.01 mmol) and biphenyl-2-yl-dicyclohexyl-phosphane (Strem
Chemicals, 11.0 mg, 0.03 mmol) in dioxane/EtOH/1M aqueous
Na.sub.2CO.sub.3 (1/1/1 3 mL) were heated and microwaved to
130.degree. C. and 300 watts for 15 minutes in an Emry.TM. Creatror
microwave. The solid was filtered off with a syringe filter and the
liquid was purified by preparative HPLC [Waters XTerra RP18 column,
30.times.100 mm, eluting solvents, MeCN 1H.sub.2O (0.1 M aqueous
ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)
(v. 90/10 to 10/90 over 20 min.), flow rate 40 mL/min, uv, 250 nm]
to provide the titled compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.96-2.17 (m, 4H), 2.20-2.52 (m, 4H), 3.71 (t, J=6.1 Hz,
1H) 3.80-3.92 (m, 2H), 6.49 (d, J=2.37 Hz, 1H), 7.10 (dd, J=8.82,
3.05 Hz, 1H), 7.25 (d, J=3.05 Hz, 1H), 7.42 (d, J=8.48 Hz, 1H),
7.56 (dd, J=8.48, 1.70 Hz, 1H), 7.63 (d, J=8.48 Hz, 1H), 7.92-8.00
(s, 1H) ppm. MS (DCI/NH.sub.3) m/z 319 (M+H).sup.+.
Example 26
[6-(4-Amino-3-methyl-phenyl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[-
3.2.1]oct-3-yl]-amine fumarate
Example 26A
[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-trifluo-
roacetamide
[0217] A mixture of
N-(4-Bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide ref US
2005-0043347, 4.23 g, 15.0 mmol), bis(pinacolato)diboron (Aldrich,
5.07 g, 20 mmol), KOAc (Aldrich, 5.27 g, 53.7 mmol) and
PdCl.sub.2(dppf):CH.sub.2Cl.sub.2(Aldrich, 203 mg, 0.25 mmol) in
anhydrous dioxane (50 mL) at 100.degree. C. for 72 hours. The
mixture was cooled to ambient temperature, diluted with EtOAc (150
mL), washed with water (2.times.25 mL). The organic solution was
concentrated under reduced pressure and the residue was purified by
chromatography (140 g SiO.sub.2, hexane:EtOAc, 80:20, R.sub.f. 0.6)
to provide the titled compound. NMR (300 MHz, CDCl.sub.3) .delta.
1.35 (s, 12H), 2.31 (s, 3H), 7.66-7.80 (m, 3H), 7.90 (d, J=8.14 Hz,
1H) ppm; MS (DCI/NH.sub.3): 347 (M+NH.sub.4).sup.+.
Example 26B
[6-(4-Amino-3-methyl-phenyl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[-
3.2.1]oct-3-yl]-amine fumarate
[0218] The product of Example 20A (130 mg, 0.52 mmol) and the
product of Example 26A (277 mg, 0.84 mmol) were treated according
to the procedure outlined in Example 8 to provide the title
compound. NMR (300 MHz, CD.sub.3OD) .delta. 2.12-2.57 (m, 11H),
2.82 (s, 3H), 3.71 (t, J=6.10 Hz, 1H), 3.85-3.94 (m, 2H), 6.69 (s,
2H), 6.77 (d, J=8.14 Hz, 1H), 7.10 (dd, J=8.65, 2.88 Hz, 1H), 7.42
(dd, J=8.14, 2.37 Hz, 1H), 7.47 (s, 1H), 7.53 (d, J=8.82 Hz, 1H),
7.92 (d, J=2.71 Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 323
(M+H).sup.+.
Example 27
[4-(1H-Indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]--
amine fumarate
Example 27A
(4-Bromo-phenyl)-(3-endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine
[0219] Tropinone (Aldrich, 2.78 g, 20 mmol) and p-bromoaniline
(Aldrich, 3.78 g, 22 mmol) were treated according to the procedure
outlined in Example 20A to provide the title compound. The title
compound was purified by chromatography (140 g SiO.sub.2,
EtOAc:MeOH (v. 2% NH.sub.3.H.sub.2O), 50:50, R.sub.f. 0.25). NMR
(300 MHz, MeOH-D4) .delta. 1.71-1.82 (m, 2H), 2.00-2.22 (m, 6H),
2.29 (s, 3H), 3.14 [s (br.), 2H], 3.46 (t, J=6.61 Hz, 1H), 6.46 (d,
J=8.81 Hz, 2H), 7.17 (d, J=9.15 Hz, 2H) ppm; MS (DCI/NH.sub.3): 297
(M+H).sup.+295 (M+H).sup.+.
Example 27B
[4-(1H-Indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]--
amine fumarate
[0220] The product of Example 27A (134 mg, 0.45 mmol) and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol (Aldrich,
198 mg, 0.81 mmol) were treated according to the procedure outlined
in Example 8 to provide the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 2.16-2.60 (m, 8H), 2.82 (s, 3H), 3.72 (t,
J=5.76 Hz, 1H), 3.89 [s (br.), 2H], 6.44 (d, J=2.37 Hz, 1H),
6.66-6.74 (m, 5.3H), 7.21 (d, J=3.39 Hz, 1H), 7.26-7.32 (m, 1H),
7.35-7.41 (m, 1H), 7.46 (d, J=8.82 Hz, 2H), 7.67 (d, J=1.02 Hz, 1H)
ppm; MS DCI/NH.sub.3): m/z 332 (M+H).sup.+; Anal. Calculated for
C.sub.22H.sub.25N.sub.3.1.65 C.sub.4O.sub.4H.sub.4: C, 65.68; H,
6.09; N, 8.03. Found: C, 65.62; H, 6.40; N, 8.14.
Example 28
[4-(1H-Indazol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl-
]-amine fumarate
[0221] The product of Example 27A (134 mg, 0.45 mmol) and the
product of Example 5A (265 mg, 1.08 mmol) were treated according to
the procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.14-2.61 (m, 8H), 2.82
(s, 3H), 3.72 (t, J=5.93 Hz, 1H), 3.89 [s (br.), 2H], 6.67-6.77 (m,
5H), 7.45-7.52 (m, 2H), 7.52-7.58 (m, 1H), 7.59-7.65 (m, 1H), 7.87
(s, 1H), 8.04 (s, 1H) ppm; MS DCI/NH.sub.3): m/z 333 (M+H).sup.+;
Anal. Calculated for C.sub.21H.sub.24N.sub.4.1.48
C.sub.4O.sub.4H.sub.4:C, 64.12; H, 5.98; N, 11.11. Found: C, 64.00;
H, 5.98; N, 11.22.
Example 29
[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-[4-(1-methyl-1H-indol-5-yl)-
-phenyl]-amine fumarate
[0222] The product of Example 27A (128 mg, 0.43 mmol) and
N-methylindole-5-boronic acid (Frontier, 142 mg, 0.81 mmol) were
treated according to the procedure outlined in Example 8 to provide
the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
2.12-2.63 (m, 8H), 2.82 (s, 3H), 3.72 (t, J=5.93 Hz, 1H), 3.80 (s,
3H), 3.88 [s (br.), 2H], 6.42 (d, J=3.05 Hz, 1H), 6.66-6.74 (m,
4H), 7.13 (d, J=3.05 Hz, 1H), 7.36 (d, J=1.0 Hz, 2H), 7.46 (d,
J=8.48 Hz, 2H), 7.67 (t, J=1.20 Hz, 1H) ppm; MS DCI/NH.sub.3): m/z
346 (M+H).sup.+. Anal. Calculated for C.sub.23H.sub.27N.sub.3.1.10
C.sub.4O.sub.4H.sub.4: C, 69.55; H, 6.69; N, 8.88. Found: C, 69.29;
H, 6.76; N, 8.85.
Example 30
(4-Benzo[b]thiophen-5-yl-phenyl-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-
-yl]-amine trifluoroacetate
[0223] The product of Example 27A (129 mg, 0.44 mmol) and
2-benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Maybridge, 189 mg, 0.73 mmol) were treated according to the
procedure outlined in Example 1B to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.17-2.60 (m, 8H), 2.82
(s, 3H), 3.73 (t, J=5.76 Hz, 1H), 3.90 [s (br.), 2H], 6.73 (d,
J=8.82 Hz, 2H), 7.38 (d, J=5.76 Hz, 1H), 7.48-7.59 (m, 4H), 7.88
(d, J=8.48 Hz, 1H), 7.97 (d, J=1.70 Hz, 1H) ppm; MS DCI/NH.sub.3):
m/z 349 (M+H).sup.+; Anal. Calculated for
C.sub.22H.sub.24N.sub.2S.1.10 C.sub.2F.sub.3O.sub.2H: C, 61.33; H,
5.34; N, 5.91. Found: C, 61.03; H, 5.34; N, 5.76.
Example 31
[4-(Benzofuran-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl-
]-amine fumarate
[0224] The product of Example 27A (135 mg, 0.46 mmol) and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran
(Maybridge, 189 mg, 0.77 mmol) were treated according to the
procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.15-2.60 (m, 8H), 2.82
(s, 3H), 3.72 (t, J=5.93 Hz, 1H), 3.88 [s (br.), 2H], 6.65-6.76 (m,
4H), 6.83 (d, J=2.71 Hz, 1H), 7.40-7.52 (m, 4H), 7.69-7.75 (m, 2H)
ppm; MS DCI/NH.sub.3): m/z 333 (M+H).sup.+; Anal. Calculated for
C.sub.22H.sub.24N.sub.2O.1.15 C.sub.4O.sub.4H.sub.4: C, 68.57; H,
6.19; N, 6.01. Found: C, 68.42; H, 6.17; N, 6.02.
Example 32
[4-(1H-Indol-4-yl]-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]--
amine fumarate
[0225] The product of Example 27A (125 mg, 0.42 mmol) and
indole-4-boronic acid (Apollo, 131 mg, 0.81 mmol) were treated
according to the procedure outlined in Example 8 to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.11-2.68
(m, 8H), 2.83 (s, 3H), 3.74 (t, J=8.31 Hz, 1H), 3.89 [s (br.), 2 HI
6.58 (dd, J=3.39, 1.02 Hz, 1H), 6.68 (s, 2H), 6.74 (d, J=8.82 Hz,
2H), 6.99 (dd, J=7.12, 1.02 Hz, 1H), 7.08-7.15 (m, 1H), 7.23 (d,
J=3.39 Hz, 1H), 7.29 (d, J=8.14 Hz, 1H), 7.51 (d, J=8.81 Hz, 2H)
ppm; MS DCI/NH.sub.3): m/z 332 (M+H).sup.+; Anal. Calculated for
C.sub.22H.sub.25N.sub.3 1.00 C.sub.4O.sub.4H.sub.4: C, 69.78; H,
6.53; N, 9.39. Found: C, 70.17; H, 6.69; N, 9.58.
Example 33
[3-(1H-Indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]--
amine fumarate
Example 33A
(3-Bromo-phenyl)-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]-amine
[0226] Tropinone (696 mg, 5.0 mmol) and m-bromoaniline (946 mg, 5.5
mmol) were treated according to the procedure outlined in Example
20A to provide the title compound. The title compound was purified
by chromatography [140 g SiO.sub.2, EtOAc:MeOH (v. 2%
NH.sub.3.H.sub.2O), 50:50, R.sub.f=0.25]. .sup.1H NMR (300 MHz,
MeOH-D.sub.4) .delta. 1.72-2.23 (m, 8H), 2.29 (s, 3H), 3.14 [s
(br.), 2H], 3.47 (t, J=6.44 Hz, 1H), 6.46-6.52 (ddd, J=8.20, 2.00,
1.00 Hz, 1H), 6.64-6.72 (m, 2H), 6.92-7.02 (t, J=8.10 Hz, 1H) ppm;
MS (DCI/NH.sub.3): 297 (M+H).sup.+, 295 (M+H).sup.+.
Example 33B
[3-(1H-Indol-5-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]--
amine fumarate
[0227] The product of Example 33A (128 mg, 0.43 mmol) and
indole-5-boronic acid (165 mg, 1.0 mmol) were treated according to
the procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.19-2.61 (m, 8H), 2.81
(s, 3H), 3.75 (t, J=5.76 Hz, 1H), 3.83-3.92 (m, 2H), 6.47 (dd,
J=3.05, 0.70 Hz, 1H), 6.55 (ddd, J=7.10, 2.60, 0.70 Hz, 1H), 6.68
(s, 2H), 6.89 (t, J=2.03 Hz, 1H), 6.96 (ddd, J=7.80, 1.70, 1.00 Hz,
1H), 7.20 (t, J=7.80 Hz, 1H), 7.24 (d, J=7.10 Hz, 1H), 7.34 (dd,
J=8.50, 1.70 Hz, 1H), 7.39 (t, J=8.40 Hz, 1H), 7.74 (dd, J=1.70,
0.70 Hz 1H) ppm; MS DCI/NH.sub.3): m/z 332 (M+H).sup.+; Anal.
Calculated for C.sub.22H.sub.25N.sub.3.1.10
C.sub.4H.sub.4O.sub.4.0.40 C.sub.4H.sub.8O.sub.2: C, 68.03; H,
6.65; N, 8.50. Found: C, 67.68; H, 6.85; N, 8.78.
Example 34
[3-(1H-Indol-4-yl)-phenyl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl]--
amine trifluoroacetate
[0228] The product of Example 33A (128 mg, 0.43 mmol) and
indole-4-boronic acid (Apollo, 168 mg, 1.0 mmol) were treated
according to the procedure outlined in Example 1B to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.22-2.64
(m, 8H), 2.81 (s, 3H), 3.74 (t, J=5.42 Hz, 1H), 3.87-3.93 (m, 2H),
6.57-6.67 (m, 2H), 6.92 (t, J=2.10 Hz, 1H), 6.99 (dt, J=7.80, 1.00
Hz, 1H) 7.14 (t, J=7.56 Hz, 1H), 7.21-7.28 (m, 2H), 7.35 (d, J=8.14
Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 332 (M+H).sup.+; Anal.
Calculated for C.sub.22H.sub.25N.sub.3.1.10 CF.sub.3CO.sub.2H.0.60
EtOH: C, 62.96; H, 6.18; N, 8.67. Found: C, 62.85; H, 5.98; N,
8.65.
Example 35
5-{6-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-2-t-
rifluoromethyl-1H-indole trifluoroacetate
[0229] The product of Example 1A (89 mg, 0.35 mmol) and the product
of Example 7A (299 mg, 0.96 mmol) were treated according to the
procedure outlined in Example 1B to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.22-2.67 (m, 8H), 2.86
(s, 3H), 3.93-4.01 [s (br), 2H], 5.55-5.62 (m, 1H), 7.02 (t, J=1.02
Hz, 1H), 7.32 (d, J=9.15 Hz, 1H), 7.60 (d, J=8.81 Hz, 1H), 7.94
(dd, J=8.82, 1.70 Hz, 1H), 8.16 (d, J=9.49 Hz, 1H), 8.26 (d, J=1.36
Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 403 (M+H).sup.+; Anal.
Calculated for C.sub.21H.sub.21F.sub.3N.sub.4O.1.53
CF.sub.3CO.sub.2H: C, 50.09; H, 3.94; N, 9.71. Found: C, 50.07; H,
3.94; N, 9.66.
Example 36
4-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-i-
ndole fumarate
[0230] The product of Example 7D (129 mg, 0.51 mmol) and
indole-4-boronic acid (Apollo, 161 mg, 1.0 mmol) were treated
according to the procedure outlined in Example 8 to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.05-2.50
(m, 6H), 2.66 (ddd, J=14.92, 5.76, 3.05 Hz, 2H), 2.85 (s, 3H), 4.03
(dd, J=3.73, 3.05 Hz, 2H), 5.67-5.83 (m, 1H), 6.79 (dd, J=3.22,
0.85 Hz, 1H), 7.22-7.30 (m, 2H), 7.37 (d, J=3.05 Hz, 1H), 7.41 (dd,
J=7.29, 0.85 Hz, 1H), 7.54 (d, J=8.14 Hz, 1H), 8.08 (d, J=9.15 Hz,
1H) ppm; MS DCI/NH.sub.3): m/z 335 (M+H).sup.+; Anal. Calculated
for C.sub.20H.sub.22N.sub.4O.1.20 C.sub.4O.sub.4: C, 62.88; H,
5.70; N, 11.83. Found: C, 62.90; H, 5.53; N, 11.79.
Example 37
5-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole fumarate
Example 37A
(exo)-3-(5-Bromo-pyridin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0231] The product of Example 7C (721 mg, 5.1 mmol) and
2,5-dibromo-pyridine (Aldrich, 1.66 g, 7.0 mmol) were treated
according to the procedure outlined in Example 1A to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.90-2.46
(m, 8H), 2.74 (s, 3H), 3.81-3.90 (m, 2H), 5.34-5.48 (m, 1H), 6.71
(d, J=8.82 Hz, 1H), 7.78 (dd, J=8.82, 2.71 Hz, 1H), 8.20 (d, J=2.37
Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 299 (M+H).sup.+297
(M+H).sup.+.
Example 37B
5-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole fumarate
[0232] The product of Example 37A (129 mg, 0.43 mmol) and
indole-5-boronic acid (Ryscor Inc., 165 mg, 1.0 mmol) were treated
according to the procedure outlined in Example 8 to provide the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.96-2.62
(m, 8H), 2.84 (s, 3H), 3.97-4.04 (m, 2H), 5.44-5.58 (m, 1H), 6.49
(dd, J=3.22, 0.85 Hz, 1H), 6.70 (s, 2H), 6.82 (d, J=8.48 Hz, 1H),
7.27 (d, J=3.05 Hz, 1H), 7.30 (dd, J=8.48, 1.70 Hz, 1H), 7.46 (d,
J=8.14 Hz, 1H), 7.73 (d, J=1.70 Hz, 1H), 7.95 (dd, J=8.65, 2.54 Hz,
1H), 8.37 (d, J=2.03 Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 334
(M+H).sup.+; Anal. Calculated for C.sub.21H.sub.23N.sub.3O.1.10
C.sub.4H.sub.4O.sub.4.1.00H.sub.2O: C, 63.67; H, 6.18; N, 8.77.
Found: C, 63.77; H, 6.26; N, 8.64.
Example 38
5-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-2-trif-
luoromethyl-1H-indole bisfumarate
[0233] The product of Example 37A (129 mg, 0.43 mmol) and
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-1H-ind-
ole (Aldrich, 319 mg, 1.02 mmol) were treated according to the
procedure outlined in Example 8 to provide the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.92-2.63 (m, 8H), 2.85
(s, 3H), 4.02 [s (br), 2H], 5.46-5.61 (m, 1H), 6.71 (s, 4H), 6.84
(d, J=8.48 Hz, 1H), 6.95 (s, 1H), 7.47-7.59 (m, 2H), 7.85 (s, 1H),
7.97 (dd, J=8.65, 2.54 Hz, 2H), 8.40 (d, J=2.03 Hz, 1H) ppm; MS
DCI/NH.sub.3): m/z 402 (M+H).sup.+. Anal. Calculated for
C.sub.22H.sub.22F.sub.3N.sub.3O.2.00C.sub.4H.sub.4O.sub.4: C,
56.87; H, 4.77; N, 6.63. Found: C, 56.98; H, 5.09; N, 6.29.
Example 39
4-{6-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridazin-3-yl}-1H-i-
ndole fumarate
[0234] The product of Example 7D (129 mg, 0.51 mmol) was coupled
with indole-4-boronic acid (Apollo, 161 mg, 1.0 mmol) to give the
free base of the title compound (150 mg, 0.45 mmol). It was then
was treated with fumaric acid (52.0 mg, 0.45 mmol) according to the
procedure of Example of 5C to give the title compound as white
solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.05-2.49 (m, 6H)
2.60-2.71 (m, 2H) 2.85 (s, 3H) 4.01-4.07 (m, 2H) 5.69-5.81 (m, 1H)
6.69 (s, 2H) 6.79 (dd, J=3.22, 0.85 Hz, 1H) 7.23-7.29 (m, 2H) 7.37
(d, J=3.05 Hz, 1H) 7.41 (dd, J=7.29, 0.85 Hz, 1H) 7.54 (d, J=8.14
Hz, 1H) 8.08 (d, J=9.15 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 335
(M+H).sup.+. Anal. Calculated for
C.sub.20H.sub.22N.sub.4O.1.2C.sub.4O.sub.4H.sub.4: C, 62.88; H,
5.70; N, 11.83. Found: C, 62.90; H, 5.53; N, 11.79.
Example 40
6-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-ind-
ole hydrochloride
Example 40A
6-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-ind-
ole
[0235] Under N.sub.2, the mixture of the product from Example 11A
(240 mg, 0.95 mmol) was coupled with 6-indolylboronic acid
(Frontier Scientific, 229 mg, 1.42 mmol) according to the procedure
of Example 11B to provide the title product. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.72-1.93 (m, 4H), 2.00-2.25 (m, 4H), 2.39 (s,
3H), 3.23-3.35 (m, 2H), 4.56-4.82 (m, 1H), 7.29 (d, J=3.05 Hz, 1H),
7.46 (d, J=2.71 Hz, 1H), 7.47-7.51 (m, 1H), 7.53 (d, J=1.36 Hz,
1H), 7.60 (d, J=8.52 Hz, 1H), 7.76 (d, J=8.82 Hz, 1H), 7.88 (s,
1H), 8.22 (d, J=3.05 Hz, 1H) ppm; MS (DCI/NH.sub.3) m/z 334
(M+H).sup.+.
Example 40B
6-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-ind-
ole hydrochloride
[0236] The product of Example 40A (210 mg, 0.63 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) EtOAc (10 mL)
at ambient temperature for 10 hours and concentrated under reduced
pressure to provide the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 2.14-2.32 (m, 2H), 2.26-2.49 (m, 4H), 2.49-2.65
(m, 2H), 2.85 (s, 3H), 3.99-4.18 (m, 2H), 5.07-5.31 (m, 1H), 6.60
(d, J=4.07 Hz, 1H), 7.46-7.56 (m, 2H), 7.82 (d, J=8.48 Hz, 1H),
7.98 (s, 1H), 8.34 (s, 1H), 8.35 (d, J=2.71 Hz, 1H), 8.55 (d,
J=2.37 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 334 (M+H).sup.+. Anal.
Calculated for C.sub.21H.sub.23N.sub.3O.1.00 HCl.1.20H.sub.2O: C,
64.42; H, 6.80; N, 10.73. Found: C, 64.54; H, 6.61; N, 10.89.
Example 41
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl)-1H-in-
dole tosylate
Example 41A
5-Bromo-pyrazin-2-ylamine
[0237] To the solution of 2-aminopyrazine (Aldrich, 4.75 g, 50
mmol) in anhydrous MeCN (Aldrich, 50 mL) was slowly added the
solution of N-bromosuccinimide (Aldrich, 8.90 g, 50 mmol) in MeCN
(anhydrous, 50 mL) at 0-10.degree. C. The reaction mixture was then
stirred at ambient temperature and quenched with saturated
Na.sub.2S.sub.2O.sub.3 (5.0 mL). The mixture was concentrated and
the residue was extracted with EtOAc (3.times.50 mL). The combined
extracts were concentrated and the title compound was purified by
chromatography (SiO.sub.2, EtOAc/hexane=1/1, v. R.sub.f=0.50).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.77 (d, J=1.36 Hz, 1H),
8.09 (d, J=1.36 Hz, 1H) ppm; m/z 174 (M+H).sup.+, 174
(M+H).sup.+.
Example 41B
5-Bromo-2-iodopyrazine
[0238] Under N.sub.2, to the mixture of the product of Example 41A
(7.50 g, 43 mmol) in DME (anhydrous, Aldrich, 200 mL) was added CsI
(Aldrich, 11.20 g, 43 mmol), iodine (Aldrich, 5.52 g, 21.6 mmol),
CuI (Stream, 2.52 g, 13.2 mmol) and isoamyl nitrite (34.8 mL, 259.2
mmol) at ambient temperature. It was then heated to 60.degree. C.
and stirred for 30 min. till no gas evolution was observed. After
being cooled down to room temperature, the dark mixtures was poured
into a flask containing EtOAc (200 mL) and saturated NH4Cl (200
mL), stirred for 10 min. The organic layer was separated and the
aqueous layer was extracted with EtOAc (2.times.1000 mL). The
combined organic solution was washed with 5% of
Na.sub.2S.sub.2O.sub.3 aqueous (2.times.50 mL), brine (50 mL) and
dried over MgS04. The drying agents were filtered off and the
organic solution was concentrated to provide the title compound.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.50 (d, J=1.36 Hz, 1H),
8.62 (d, J=1.36 Hz, 1H) ppm; m/z 284 (M+H).sup.+, 286
(M+H).sup.+.
Example 41C
(endo)-3-(5-Iodo-pyrazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0239] Under N.sub.2, the mixture of (endo)-tropine (Aldrich, 1.54
g, 11 mmol) was treated with potassium t-butoxide (Aldrich, 0.96 g,
10 mmol) in THF (anhydrous, Aldrich, 50 mL) at ambient temperature
for 1 h. The product of Example 41B (2.85 g, 10.0 mmol) and was
added. The brown mixture was stirred at ambient temperature for 4
hours and quenched with water (5 mL). The mixture was concentrated
and the residue was purified by chromatography (150 g SiO.sub.2,
EtOAc:MeOH:NH.sub.3.H.sub.2O, 90:10:1, R.sub.f. 0.20) to give the
title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 6
2.16-2.60 (m, 8H), 2.84 (s, 3H), 3.78-4.05 (m, 2H), 5.17-5.40 (m,
1H), 8.14 (d, J=1.36 Hz, 1H), 8.42 (d, J=1.36 Hz, 1H) ppm; MS
(DCI/NH.sub.3) m/z 346 (M+H).sup.+.
Example 41D
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole
[0240] The product from Example 41C (200 mg, 0.58 mmol), was
coupled with 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol)
according to the procedure of 1 Example 9B to provide the title
product. .sup.1H NMR (300 MHz, CD.sub.3OD) 6 1.94-2.05 (m, 2H),
2.07-2.29 (m; 6H), 2.34 (s, 3H), 3.15-3.27 (m, 2H), 5.29 (t, J=5.09
Hz, 1H), 6.53 (d, J=2.37 Hz, 1H), 7.27 (d, J=3.39 Hz, 1H), 7.47 (d,
J=8.48 Hz, 1H), 7.68 (dd, J=8.48, 1.70 Hz, 1H), 8.11 (s, 1H), 8.17
(d, J=1.70 Hz, 1H), 8.58 (d, J=1.36 Hz, 1H) ppm. MS (DCI/NH.sub.3)
m/z 335 (M+H).sup.+.
Example 41E
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole tosylate
[0241] The product of Example 41D (90 mg, 0.27 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 57
mg, 0.3 mmol) in EtOAcIEtOH (v. 4:1, 5 mL) at ambient temperature
for 10 hour. The mixture was concentrated under reduced pressure to
provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.36 (s, 3H), 2.38-2.48 (m, 4H), 2.48-2.61 (m, 4H), 2.84
(s, 3H), 3.84-4.05 (m, 2H), 5.41 (t, J=4.41 Hz, 1H), 7.23 (d,
J=7.80 Hz, 2H), 7.30 (s, 1H), 7.49 (d, J=8.48 Hz, 1H), 7.65-7.77
(m, 4H), 8.13 (d, J=1.70 Hz, 1H), 8.29 (s, 1H) ppm. MS
(DCI/NH.sub.3):m/z 335 (M+H).sup.+. Anal. Calculated for
C.sub.20H.sub.22N.sub.4O.1.38 C.sub.7H.sub.8SO.sub.3.0.80H.sub.2O:
C, 60.74; H, 5.95; N, 9.55. Found: C, 61.00; H, 5.63; N, 9.17.
Example 42
4-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole bistosylate
Example 42A
4-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole
[0242] The product from Example 41C (200 mg, 0.58 mmol), was
coupled with 4-indolylboronic acid (Apollo, 143.3 mg, 0.89 mmol)
according to the procedure of Example 9B to provide the title
compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.97-2.06 (m,
2H), 2.08-2.30 (m, 6H), 2.34 (s, 3H), 3.16-3.28 (m, 2H), 5.33 (t,
J=5.09 Hz, 1H), 6.82 (d, J=3.39 Hz, 1H), 7.22 (t, J=7.50 Hz, 1H),
7.34 (d, J=3.05 Hz, 1H), 7.40 (d, J=7.46 Hz, 1H), 7.47 (d, J=8.14
Hz, 1H), 8.27 (d, J=1.36 Hz, 1H), 8.61 (d, J=1.36 Hz, 1H) ppm. MS
(DCI/NH.sub.3) m/z 335 (M+H).sup.+.
Example 42B
4-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole bistosylate
[0243] The product of Example 42A (40 mg, 0.12 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 27
mg, 0.15 mmol) in EtOAc/EtOH (v. 4:1, 5 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.36 (s, 6H) 2.40-2.48 (m, 4H), 2.50-2.64 (m, 2H), 2.85 (s,
3H), 3.87-4.04 (m, 2H), 5.26-5.63 (m, 1H), 7.19-7.29 (m, 6H), 7.35
(s, 1H), 7.42 (d, J=6.44 Hz, 1H), 7.49 (d, J=8.14 Hz, 1H), 7.71 (d,
J=8.48 Hz, 4H), 8.38 (d, J=1.36 Hz, 1H), 8.68 (d, J=1.36 Hz, 1H)
ppm. MS (DCI/NH.sub.3): m/z 335 (M+H).sup.+. Anal. Calculated for
C.sub.20H.sub.22N.sub.4O.2.00 C.sub.7H.sub.8SO.sub.3.0.50H.sub.2O:
C, 59.37; H, 5.71; N, 8.15. Found: C, 59.56; H, 6.10; N, 8.17.
Example 43
6-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole tosylate
Example 43A
6-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole
[0244] The product from Example 41C (200 mg, 0.58 mmol), was
coupled with 6-indolylboronic acid (Frontier Scientific, 143.3 mg,
0.89 mmol) according to the procedure of Example 9B to provide the
title product. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.93-2.05
(m, 2H), 2.08-2.28 (m, 6H), 2.33 (s, 3H), 3.13-3.26 (m, 2H), 5.29
(t, J=4.92 Hz, 1H), 6.47 (d, J=3.05 Hz, 1H), 7.30 (d, J=3.39 Hz,
1H), 7.54-7.68 (m, 2H), 7.96 (s, 1H), 8.19 (d, J=1.36Hz, 1H), 8.60
(d, J=1.36 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 335 (M+H).sup.+.
Example 43B
6-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-in-
dole tosylate
[0245] The product of Example 43A (80 mg, 0.24 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 57
mg, 0.30 mmol) in EtOAc/EtOH (v. 4:1, 5 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.36 (s, 3H), 2.37-2.48 (m, 6H), 2.47-2.63 (m, 2H), 2.84
(s, 3H), 3.83-4.02 (m, 2H), 5.27-5.50 (m, 1H), 6.48 (d, J=2.37 Hz,
1H), 7.32 (t, J=1.70 Hz, 1H), 7.53-7.67 (m, 2H), 7.71 (d, J=8.14
Hz, 2H), 7.99 (s, 1H), 8.29 (d, J=1.36 Hz, 1H), 8.64 (d, J=1.36 Hz,
1H) ppm. MS (DCI/NH.sub.3): m/z 335 (M+H).sup.+. Anal. Calculated
for C.sub.20H.sub.22N.sub.4O.1.15
C.sub.7H.sub.8SO.sub.3.0.75H.sub.2O: C, 61.71; H, 6.04; N, 10.26.
Found: C, 61.74; H, 5.72; N, 9.87.
Example 44
[6-(1H-Indol-6-yl)-pyridin-3-yl]-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct--
3-yl]-amine trifluoroacetate
[0246] The product of Example 20A (139 mg, 0.55 mmol) was coupled
with indole-6-boronic acid (Frontier Scientific, 165 mg, 1.02 mmol)
according to the procedure of Example 8 to provide the title
compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.18-2.63 (m,
8H) 2.84 (s, 3H) 3.82 (t, J=6.10 Hz, 1H) 3.96 (s, 2H) 6.57 (dd,
J=3.05, 0.68 Hz, 1H) 7.41-7.47 (m, 2H) 7.74-7.93 (m, 4H) 8.10 (d,
J=9.16 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 333 (M+H).sup.+. Anal.
Calculated for C.sub.21H.sub.24N.sub.4.2.45 CF.sub.3CO.sub.2H: C,
50.85; H, 4.36; N, 9.16. Found: C, 50.72; H, 4.43; N, 9.25.
Example 45
5-{6-[(endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yloxy]pyridazin-3-yl}-1H--
indole trifluoroacetate
Example 45A
(endo)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-ol
[0247] (endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-wola s prepared
according to the procedure as described in WO 03062235. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.22-1.32 (m, 2H), 1.35-1.47 (m, 3H),
1.98 (tt, J=13.60, 5.21 Hz, 2H), 2.30-2.56 (m, 6H), 2.87-2.96 (m,
2H), 4.04-4.15 (m, 1H) ppm. MS (DCI/NH.sub.3): m/z 156 (M+H)+.
Example 45B
(endo)-3-(6-chloropyridazin-3-yloxy)-9-methyl-9-azabicyclo[3.3.1]nonane
[0248] The product of Example 45A (467 mg, 3.0 mmol) was coupled
with 3,6-dichloropyridazine (614 mg, 3.3 mmol) according to the
procedure of Example 1A. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.59 (ddd, J=14.41, 6.27, 6.10 Hz, 1H), 1.77 (dd, J=14.92, 5.76 Hz,
2H), 2.06-2.28 (m, 4H), 2.52-2.82 (m, 3H), 2.90 (s, 3H), 3.51 (t,
J=5.76 Hz, 2H), 5.55 (tt, J=6.91, 1.74 Hz, 1H), 7.26 (d, J=9.16 Hz,
1H), 7.69 (d, J=9.16 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 268
(M+H).sup.+.
Example 45C
5-{6-[(endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yloxy]pyridazin-3-yl}-1H--
indole trifluoroacetate
[0249] The product of Example 45B (145 mg, 0.54 mmol) was coupled
with indole-5-boronic acid (Ryscor, 165 mg, 1.02 mmol) according to
the procedure of Example 1B to provide the title compound. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. 1.57-1.1 (m, 2H) 1.95-2.47 (m,
5H) 2.67-2.92 (m, 3H) 2.98-3.06 (m, 3H) 3.65 (t, J=5.09 Hz, 2H)
5.61 (t, J=6.95 Hz, 1H) 6.59 (d, J=3.05 Hz, 1H) 7.34 (d, J=3.05 Hz,
1H) 7.37-7.43 (m, 1H) 7.55 (d, JS.48 HZ, 1H) 7.74 (dd, JS.65, 1.86
HZ, 1H) 8.18 (d, J=1.70 HZ, 1H) 8.20-8.27 (m, 1H) ppm. MS
(DCI/NH.sub.3): m/z 349 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.24N.sub.4O.2.10 CF.sub.3CO.sub.2H: C, 51.48; H, 4.47;
N, 9.53. Found: C, 51.31; H, 4.33; N, 9.36.
Example 46
(endo)-3-[6-(Benzo[b]thiophen-5-yl)pyridazin-3-yloxy]-9-methyl-9-azabicycl-
o[3.3.1]nonane trifluoroacetate
[0250] The product of Example 45B (145 mg, 0.54 mmol) was coupled
with the product of 10A (280 mg, 1.02 mmol) according to the
procedure of Example 1B to provide the title compound. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.56-1.81 (m, 2H), 1.94-2.48 (m, 5H),
2.68-2.92 (m, 3H), 2.98-3.08 (m, 3H), 3.65 (t, J=5.09 Hz, 2H), 5.66
(t, J=6.95 Hz, 1H), 7.34 (d, J=9.16 Hz, 1H), 7.50 (d, J=5.76 Hz,
1H), 7.68 (d, J=5.76 Hz, 1H), 7.96-8.02 (m, 1H), 8.04-8.10 (m, 1H),
8.20 (d, J=9.49 Hz, 1H), 8.45 (d, J=1.36 Hz, 1H) ppm. MS
(DCI/NH.sub.3): m/z 366 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.23N.sub.3O.S1.13 CF.sub.3CO.sub.2H: C, 56.51; H,
4.92; N, 8.50. Found: C, 56.56; H, 4.75; N, 8.44.
Example 47
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-py-
rrolo[2,3-b]pyridine bistosylate
Example 47A
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0251] 5-Bromo-1H-pyrrolo[2,3-b]pyridin (eC hemgenx, 0.90 g, 4.57
mmol) was coupled with bis(pinacolato)diboron (Aldrich, 1.27 g, 5.0
mmol) according to the procedure of Example 10A. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 1.37 (s, 12H) 6.52 (d, J=3.73 Hz, 1H),
7.38 (d, J=3.73 Hz, 1H), 8.34 (d, J=1.36 Hz, 1H), 8.49 (d, J=1.70
Hz, 1H) ppm; m/z 245 (M+H).sup.+.
Example 47B
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-py-
rrolo[2,3-b]pyridine tosylate
[0252] The product from Example 41C (207 mg, 0.60 mmol), was
coupled with the product of Example 47A (200.0 mg, 0.82 mmol)
according to the procedure of Example 10B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.98-2.09 (m, 2H), 2.10-2.32 (m, 6H), 2.40 (s,
3H), 5.32 (t, J=5.09 Hz, 1H), 6.58 (d, J=3.39 Hz, 1H), 7.44 (d,
J=3.73 Hz, 1H), 8.25 (d, J=1.36 Hz, 1H), 8.53 (d, J=2.03 Hz, 1H),
8.65 (d, J=1.36 Hz, 1H), 8.78 (d, J=2.03 Hz, 1H) ppm. MS
(DCI/NH.sub.3) m/z 336 (M+H).sup.+.
Example 47C
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-py-
rrolo[2,3-b]pyridine bistosylate
[0253] The product of Example 47B (90 mg, 0.27 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.20 (Aldrich, 95
mg, 0.5 mmol) in EtOAc/EtOH (v. 4:1, 10 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.35 (s, 6H), 2.38-2.45 (m, 2H), 2.45-2.61 (m, 6H), 2.85
(s, 3H), 3.85-4.07 (m, 2H), 5.46 (t, J=4.75 Hz, 1H), 6.97 (d,
J=3.39 Hz, 1H), 7.22 (d, J=7.80 Hz, 4H) 7.70 (d, J=8.14 Hz, 4H),
7.76 (d, J=3.73 Hz, 1H), 8.42 (d, J=1.36 Hz, 1H), 8.85 (d, J=1.36
Hz, 1H), 9.04 (d, J=1.70 Hz, 1H), 9.27 (d, J=1.70 Hz, 1H) ppm. MS
(DCI/NH.sub.3): m/z 336 (M+H).sup.+. Anal. Calculated for
C.sub.19H.sub.21N.sub.5O.2.17 C.sub.7H.sub.8SO.sub.3.1.00H.sub.2O:
C, 56.48; H, 5.59; N, 9.63. Found: C, 56.48; H, 5.37; N, 9.67.
Example 48
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-pyr-
rolo[2,3-b]pyridine bistosylate
Example 48A
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-pyr-
rolo[2,3-b]pyridine
[0254] The product from Example 11A (152 mg, 0.60 mmol), was
coupled with the product of Example 47A (200.0 mg, 0.82 mmol)
according to the procedure of Example 9B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.76-1.92 (m, 4H), 2.06-2.20 (m, 4H), 2.36 (s,
3H), 3.18-3.31 (m, 2H), 4.64-4.79 (m, 1H), 6.57 (d, J=3.39 Hz, 1H),
7.43 (d, J=3.73 Hz, 1H), 7.8 1 (d, J=8.82 Hz, 1H), 8.29 (d, J=3.05
Hz, 1H), 8.45 (d, J=2.03 Hz, 1H), 8.72 (d, J=2.03 Hz, 1H) ppm. MS
(DCI/NH.sub.3) m/z 335 (M+H).sup.+.
Example 48B
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-pyr-
rolo[2,3-b]pyridine bistosylate
[0255] The product of Example 48A (100 mg, 0.30 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.20 (Aldrich, 95
mg, 0.5 mmol) in EtOAc/EtOH (v. 4:1, 10 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.18-2.47 (m, 2H), 2.15-2.40 (m, 10H), 2.46-2.60 (m, 2H),
2.85 (s, 3H), 3.99-4.06 (m, 2H), 4.95-5.19 (m, 1H), 6.83 (d, J=3.39
Hz, 1H), 7.22 (d, J=8.14 Hz, 4H), 7.66 (d, J=3.39 Hz, 1H), 7.70 (d,
J=8.48 Hz, 4H), 8.09 (d, J=8.82 Hz, 1H), 8.48 (d, J=2.71 Hz, 1H),
8.87 (d, J=2.03 Hz, 1H), 8.91 (d, J=2.03 Hz, 1H) ppm. MS
(DCI/NH.sub.3): m/z 335 (M+H).sup.+. Anal. Calculated for
C.sub.20H.sub.22N.sub.4O.2.14 C.sub.7H.sub.8SO.sub.3.0.50H.sub.2O:
C, 59.01; H, 5.68; N, 7.87. Found: C, 58.88; H, 5.63; N, 7.47.
Example 49
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole tri(hydrochloride)
Example 49A
(exo)-3-(5-Chloro-pyridin-3-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0256] (endo)-Tropine (Aldrich, 0.56 g, 4.0 mmol), was coupled with
3-chloro-5-hydroxy-pyridine (Aldrich, 0.26 g, 2.0 mmol), in the
presence of DIAD (di-isopropyl azadicarboxylate, Aldrich, 0.81 g,
4.0 mmol) and Ph3P (Aldrich, 1.14 g, 4.0 mmol) in THF (anhydrous,
Aldrich, 20 mL) at ambient temperature for two days. The reaction
mixture was concentrated. The title product was purified by
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.3.H.sub.2O,
90:10:1, R.sub.f. 0.45). NMR (300 MHz, CD.sub.3OD) 1.66-1.91 (m,
4H), 1.98-2.19 (m, 4H), 2.33 (s, 3H), 3.22-3.28 (m, 2H), 4.58-4.79
(m, 1H), 7.49 (dd, J=2.37, 1.70 Hz, 1H), 8.11 (d, J=1.70 Hz, 1H),
8.15 (d, J=2.37 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 255 (M+H).sup.+,
253 (M+H).sup.+.
Example 49B
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole
[0257] Under N.sub.2, the mixture of the product from Example 49A
(250 mg, 1.00 mmol) was coupled with 5-Indolylboronic acid (Rsycor,
240.0 mg, 1.50 mmol) according to the procedure of Example 9B.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.71-1.92 (m, 4H),
2.02-2.21 (m, 4H), 2.34 (s, 3H), 3.23-3.30 (m, 2H), 4.63-4.80 (m,
1H), 6.54 (d, J=3.05 Hz, 1H), 7.29 (d, J=3.39 Hz, 1H), 7.38 (dd,
J=8.48, 2.03 Hz, 1H), 7.47-7.53 (m, 1H), 7.58-7.64 (m, 1H), 7.83
(d, J=1.36 Hz, 1H), 8.15 (d, J=2.71 Hz, 1H), 8.39 (d, J=1.70 Hz,
1H) ppm. MS (DCI/NH.sub.3) m/z 334 (M+H).sup.+.
Example 49C
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-3-yl}-1H-ind-
ole tri(hydrochloride)
[0258] The product of Example 49B (90 mg, 0.27 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.25 mL, 1.0 mmol) in
.sup.iPrOAc/.sup.iPrOH (v. 4:1, 5 mL) at ambient temperature for 2
hours to provide the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 2.01-2.66 (m, 8H), 2.83 (s, 3H), 3.92-4.09 (m,
2H), 4.98-5.15 (m, 1H), 6.61 (d, J=3.05 Hz, 1H), 7.33-7.40 (m, 1H),
7.50-7.63 (m, 2H), 8.04-8.10 (m, 2H), 8.44 (d, J=1.70 Hz, 1H), 8.80
(s, 1H) ppm. MS (DCI/NH.sub.3): m/z 334 (M+H).sup.+. Anal.
Calculated for C.sub.21H.sub.23N.sub.3O.3.00 HCl. 4.60H.sub.2O: C,
47.98; H, 6.14; N, 7.85. Found: C, 47.62; H, 6.38; N, 7.62.
Example 50
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole tosylate
Example 50A
(exo)-3-(5-Iodo-pyrazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
[0259] Under N.sub.2, the mixture of product from 7C (0.42 g, 3.0
mmol) was treated with potassium t-butoxide (Aldrich, 0.32 g, 3.3
mmol) in THF (anhydrous, Aldrich, 50 mL) at ambient temperature for
1 hours. The product of Example 41B (1.00 g, 3.5 mmol) and was
added. The mixture was stirred at ambient temperature for 4 hours
and quenched with water (5 mL). The mixture was concentrated and
the residue was purified by chromatography (150 g SiO.sub.2,
EtOAc:MeOH:NH.sub.3.H.sub.2O, 90:10:1, R.sub.f. 0.40) to provide
the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.90-2.25 (m, 4H), 2.31-2.60 (m, 4H), 2.84 (s, 3H), 3.94-4.11 (m,
2H), 5.32-5.57 (m, 1H), 8.06 (d, J=1.36 Hz, 1H), 8.42 (d, J=1.36
Hz, 1H) ppm; MS (DCI/NH.sub.3) m/z 346 (M+H).sup.+.
Example 50B
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole
[0260] The product from Example 50A (200 mg, 0.58 mmol), was
coupled with 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol)
according to the procedure of Example 9B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.95-2.17 (m, 2H), 2.16-2.31 (m, 2H), 2.36-2.47
(m, 2H), 2.48-2.67 (m, 2H), 2.85 (s, 3H), 3.90-4.17 (m, 1H),
5.36-5.69 (m, 1H), 6.53 (d, J=3.39 Hz, 1H), 7.29 (d, J=3.05 Hz,
1H), 7.48 (d, J=8.48 Hz, 1H) 7.69 (dd, J=8.48, 1.70 Hz, 1H), 8.13
(s, 1H) 8.20 (d, J=1.36 Hz, 1H), 8.62 (d, J=1.36 Hz, 1H) ppm. MS
(DCI/NH.sub.3) m/z 335 (M+H).sup.+.
Example 50C
5-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole tosylate
[0261] The product of Example 50B (170 mg, 0.50 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.20 (Aldrich, 100
mg, 0.51 mmol) in EtOAc/EtOH (v. 4:1, 5 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.01-2.15 (m, 2H), 2.16-2.30 (m, 2H), 2.36 (s, 3H),
2.39-2.49 (m, 2H), 2.52-2.67 (m, 2H), 2.84 (s, 3H), 3.96-4.13 (m,
2H), 5.43-5.70 (m, 1H), 7.23 (d, J=8.14 Hz, 2H), 7.30 (s, 1H), 7.49
(d, J=8.48 Hz, 1H), 7.62-7.75 (m, 4H), 8.12 (s, 1H), 8.22 (d,
J=1.36 Hz, 1H), 8.68 (d, J=1.36 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z
335 (M+H).sup.+.
Example 51
4-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole tosylate
Example 51A
4-{5-[(exo]-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole
[0262] The product from Example 50A (200 mg, 0.58 mmol), was
coupled with 4-indolylboronic acid (Apollo, 143.3 mg, 0.89 mmol)
according to the procedure of Example 9B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 2.02-2.28 (m, 4H), 2.34-2.48 (m, 2H), 2.50-2.65
(m, 2H), 2.86 (s, 3H), 3.96-4.07 (m, 2H), 5.45-5.68 (m, 1H), 6.82
(d, J=4.07 Hz, 1H), 7.23 (t, J=7.60 Hz 1H), 7.35 (d, J=3.39 Hz,
1H), 7.41 (d, J=6.44 Hz, 1H), 7.48 (d, J=8.14 Hz, 1H), 8.29 (d,
J=1.36 Hz, 1H), 8.65 (d, J=1.36 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z
335 (M+H).sup.+.
Example 51B
4-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-yl]-1H-indol-
e tosylate
[0263] The product of Example 51A (120 mg, 0.36 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.2O (Aldrich, 68
mg, 0.36 mmol) in EtOAc/EtOH (v. 4:1, 5 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.02-2.17 (m, 2H), 2.18-2.32 (m, 2H), 2.36 (s, 3H),
2.38-2.50 (m, 2H), 2.52-2.69 (m, 2H), 2.85 (s, 3H), 4.00-4.11 (m,
2H), 7.17-7.28 (m, 1H), 7.35 (s, 1H), 7.42 (d, J=7.12 Hz, 1H), 7.49
(d, J=8.14 Hz, 1H), 7.70 (d, J=8.14 Hz, 1H), 8.30 (d, J=1.70 Hz,
1H), 8.67 (d, J=1.36 Hz, 1H) ppm. MS (DCI/NH.sub.3): m/z 335
(M+H).sup.+.
Example 52
6-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole tosylate
Example 52A
6-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole
[0264] The product from Example 41C (200 mg, 0.58 mmol), was
coupled with 6-indolylboronic acid (Frontier Scientific, 143.3 mg,
0.89 mmol) according to the procedure of Example 9B. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.97-2.16 (m, 2H), 2.14-2.26 (m, 2H),
2.31-2.65 (m, 4H), 2.81 (s, 3H), 3.84-4.05 (m, 2H), 5.33-5.71 (m,
1H), 6.47 (d, J=3.05 Hz, 1H), 7.31 (d, J=3.05 Hz, 1H), 7.48-7.73
(m, 2H), 7.99 (s, 1H), 8.20 (d, J=1.36 Hz, 1H), 8.63 (d, J=1.36 Hz,
1H) ppm. MS (DCI/NH.sub.3) m/z 335 (M+H).sup.+.
Example 52B
6-{5-[(exo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyrazin-2-yl}-1H-ind-
ole tosylate
[0265] The product of Example 52A (90 mg, 0.27 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.20 (Aldrich, 57
mg, 0.30 mmol) in EtOAc/EtOH (v. 4:1, 5 mL) at ambient temperature
for 10 hours. The mixture was concentrated under reduced pressure
to provide the title compound. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 2.01-2.14 (m, 2H), 2.16-2.31 (m, 2H), 2.36 (s, 3H),
2.39-2.51 (m, 2H), 2.50-2.65 (m, 2H), 2.84 (s, 3H), 3.98-4.08 (m,
2H), 5.41-5.68 (m, 1H), 6.48 (d, J=2.37 Hz, 1H), 7.23 (d, J=7.80
Hz, 2H), 7.32 (s, 1H), 7.55-7.67 (m, 2H), 7.71 (d, J=8.48 Hz, 2H),
7.99 (s, 1H), 8.22 (d, J=1.36 Hz, 1H), 8.65 (d, J=1.36 Hz, 1H) ppm.
MS (DCI/NH.sub.3): m/z 335 (M+H).sup.+.
Example 53
(endo)-N-(5-(1H-Indol-5-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine
Example 53A
(endo)-N-(5-Bromopyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine
[0266] 8-Methyl-8-azabicyclo[3.2.1]octan-3-one (Aldrich, 695 mg,
5.0 mmol) reacted with bromopyridin-3-amine (950 mg, 5.5 mmol)
according to the procedure of Example 20A to give the title
compound (650 mg, yield, 44%). .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.54-2.25 (m, 8H), 2.29 (s, 3H), 3.16 [s (broad), 2H], 3.50
(t, J=6.61 Hz, 1H), 7.08 (t, J=2.20 Hz, 1H), 7.79 (d, J=1.70 Hz,
1H), 7.85 (d, J=2.37 Hz, 1H) ppm; MS (DCI/NH.sub.3): m/z 298
(M+H).sup.+, 296 (M+H).sup.+.
Example 53B
(endo)-N-(5-(1H-Indol-5-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine p-tosylate
[0267] The product of Example 53A (150 mg, 0.5 mmol) was coupled
with indole-5-boronic acid (Frontier, 150 mg, 0.93 mmol) according
to the procedure of Example 9B to provide the free base of the
title compound (82 mg, yield, 50%), which was treated with
p-toluenesulfonic acid hydrate (Aldrich, 47 mg, 0.25 mmol) in
EtOAc/EtOH (v. 10:1, 5 mL) at room temperature for 16 hours. The
precipitate was collected and dried to give the title compound
(99.3 mg, yield, 67.2%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
2.15-2.30 (m, 2H), 2.30-2.42 (m, 5.5H), 2.42-2.63 (m, 4H), 2.82 (s,
3H), 3.81 (t, J=5.9 Hz, 1H), 3.93 [s (broad), 2H), 6.54 (d, J=2.4
Hz, 1H), 7.21 (d, J=8.1 Hz, 3H), 7.32 (d, J=3.1 Hz, 1H), 7.39 (dd,
J=8.4, 1.7 Hz, 1H), 7.47-7.59 (m, 2H), 7.70 (d, J=8.5 Hz, 3H), 7.86
(d, J=1.7 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 8.23 (d, J=1.7 Hz, 1H)
ppm. MS DCI/NH.sub.3): m/z 333 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.24N.sub.4.1. 50C.sub.7H.sub.8O.sub.3S.1.2 0H.sub.2O:
C, 61.78; H, 6.32; N, 9.15. Found: C, 61.78; H, 6.19; N, 8.99.
Example 54
(endo)-N-(5-(1H-Indol-4-yl)pyridin-3-yl)-8-methy
1-8-azabicyclo[3.2.1]octan-3-amine p-tosylate
Example 54A
(endo)-N-(5-(1H-Indol-4-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine
[0268] The product of Example 53A (150 mg, 0.5 mmol) was coupled
with indole-4-boronic acid (Frontier, 150 mg, 0.93 mmol) according
to the procedure of Example 9B to provide the title compound (80
mg, yield, 48%), .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.78-1.96 (m, 2H), 2.05-2.16 (m, 4H), 2.17-2.30 (m, 2H), 2.33 (s,
3H), 3.21 [s (broad), 2H], 3.63 (t, J=6.8 Hz, 1H), 6.57 (d, J=3.4
Hz, 1H), 7.08 (d, J=7.1 Hz, 1H), 7.15-7.26 (m, 2H), 7.31 (d, J=3.1
Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.89 (d, J=2.7 Hz, 1H), 8.05 (d,
J=1.7 Hz, 1H) ppm; MS DCI/NH.sub.3): m/z 333 (M+H).sup.+.
Example 54B
(endo)-N-(5-(1H-Indol-4-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine p-tosylate
[0269] The product of Example 54A (80 mg, 0.24 mmol) was treated
with ptoluenesulfonic acid hydrate (Aldrich, 47 mg, 0.25 mmol) in
EtOAc/EtOH (v. 10:1, 5 mL) at room temperature for 16 hours. The
precipitate was collected and dried to give the title compound
(85.3 mg, yield, 58.5%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
2.17-2.31 (m, 2H), 2.31-2.41 (m, 5.8H), 2.41-2.60 (m, 4H), 2.82 (s,
3H), 3.79 (t, J=5.9 Hz, 1H), 3.93 [s (broad), 2H), 7.16 (dd, J=7.5,
1.0 Hz, 1H), 7.21-7.27 (m, 5.2H), 7.37 (d, J=3.1 Hz, 1H), 7.50 (d,
J=8.1 Hz, 1.0H), 7.62-7.66 (m, 1.0H), 7.70 (d, J=8.1 Hz, 3.2H),
7.99 (d, J=2.4 Hz, 1H), 8.24 (d, J=1.4 Hz, 1H) ppm. MS
DCI/NH.sub.3): m/z 333 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.24N.sub.4.1.60C.sub.7H.sub.8O.sub.3S.1.20H.sub.2O: C,
61.43; H, 6.28; N, 8.90. Found: C, 6 1.72; H, 6.26; N, 8.64.
Example 55
(endo)-N-(5-(1H-Indol-6-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine p-tosylate
Example 55A
(endo)-N-(5-(1H-Indol-6-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine
[0270] The product of Example 53A (150 mg, 0.5 mmol) was coupled
with indole-6-boronic acid (Frontier, 150 mg, 0.93 mmol) according
to the procedure of Example 9B to provide the free base of the
title compound (102 mg, yield, 60%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.80-1.98 (m, 2H), 2.06-2.19 (m, 4H), 2.19-2.32
(m, 2H), 2.35 (s, 3H), 3.24 [s (broad), 2H), 3.64 (t, J=6.8 Hz,
1H), 6.47 (d, J=3.4 Hz, 1H), 7.16-7.21 (m, 1H), 7.22-7.34 (m, 2H),
7.57-7.67 (m, 2H), 7.83 (d, J=2.7 Hz, 1H), 8.06 (d, j=2.0 Hz, 1H)
ppm; MS DCI/NH.sub.3): m/z 333 (M+H).sup.+.
Example 55B
(endo)-N-(5-(1H-Indol-6-yl)pyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-
-3-amine p-tosylate
[0271] The product of Example 55A (102 mg, 0.3 mmol) was treated
with ptoluenesulfonic acid hydrate (Aldrich, 57 mg, 0.30 mmol) in
EtOAc/EtOH (v. 10:1, 5 mL) at room temperature for 16 hours. The
precipitate was collected and dried to give the title compound
(137.2 mg, yield, 59.4%). .sup.1H NMR (300 MHz, CD.sub.3OD)
2.16-2.64 (m, 12.2H), 2.82 (s, 3H), 3.78 (t, J=6.3 Hz, 1H), 3.92 [s
(broad), 2H), 6.48 (d, J=4.1 Hz, 1H), 7.22 (d, J=7.8 Hz, 2.8H),
7.27 (dd, J=8.1, 1.7 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.31-7.34 (m,
1H), 7.61-7.66 (m, 2H), 7.70 (d, J=8.1 Hz, 2.8H), 7.88 (d, J=2.4
Hz, 1H), 8.17 (d, J=1.7 Hz, 1H) ppm. MS DCI/NH.sub.3): m/z 333
(M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.24N.sub.4.1.40C.sub.7H.sub.8O.sub.3S.0.70H.sub.2O: C,
63.11; H, 6.29; N, 9.56. Found: C, 63.17; H, 6.61; N, 9.43.
Example 56
(endo)-N-{5-[2-(trifluoromethyl)-1H-indol-5-yl]pyridin-3-yl}-8-Methyl-8-az-
abicyclo[3.2.1]octan-3-amine fumarate
[0272] The product of Example 9A (1 10 mg, 0.4 mmol) was coupled
with the product of Example 7A (300 mg, 0.97 mmol) according to the
procedure described in Example 9B to provide the free base of the
title compound (38 mg, yield, 22.5%), which was (38 mg 0.09 mmol)
was then treated with fumaric acid (12 mg, 0.1 mmol) in EtOAc/EtOH
(v. 10:1, 5 mL) at room temperature for 16 hours. The precipitate
was filtered and dried to give the title compound (50.4 mg, yield,
99%). .sup.1H NMR (300 MHz, CD.sub.3OD) S 2.28-2.37 (m, 4H),
2.42-2.57 (m, 4H), 2.84 (s, 3H), 3.02 broad), 2 HI, 4.80-4.90 (m,
1H) 6.72 (s, 2.6H), 6.97 (s, 1H), 7.47-7.57 (m, 2H), 7.85 (d, J=8.8
Hz, 2H), 8.17 (s, 1H) 8.30 (s, 1H) ppm. MS DCI/NH.sub.3): m/z 402
(M+H).sup.+. Anal. Calculated for
C.sub.22H.sub.22F.sub.3N.sub.4O.1.30C.sub.4O.sub.4H.sub.4: C,
59.15; H, 4.96; N, 7.61. Found: C, 59.29; H, 5.07; N, 7.37.
Example 57
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-py-
rrolo[2,3-b]pyridine tosylate
Example 57A
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-py-
rrolo[2,3-b]pyridine
[0273] The product of Example 9A (200 mg, 0.80 mmol), was coupled
with the product of Example 47A (244.0 mg, 1.0 mmol) according to
the procedure of Example 9B. to provide the title compound (190 mg,
yield, 71%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.93-2.27
(m, 8H), 2.33 (s, 3H), 3.20 [s (broad.), 2H], 4.69 (t, J=5.1 Hz,
1H), 6.57 (d, J=3.4 Hz, 1H), 7.39-7.48 (m, 2H), 7.83 (d, J=8.5 Hz,
1H), 8.25 (d, J=2.7 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.4
Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 335 (M+H).sup.+.
Example 57B
5-{5-[(endo)-8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]-pyridin-2-yl}-1H-py-
rrolo[2,3-b]pyridine tosylate
[0274] The product of Example 48A (80 mg, 0.24 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.20 (Aldrich, 57
mg, 0.3 mmol) in EtOAc/EtOH (v. 4:1, 10 mL) at ambient temperature
for 10 hours. The precipitated solid was filtered and dried to
provide the title compound (100 mg, yield, 79.6%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 2.27-2.69 (m, 11H), 2.84 (s, 3H),
3.84-4.08 (m, 2H), 4.84-4.94 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 7.23
(d, J=8.1 Hz, 2H), 7.47 (d, J=3.7 Hz, 1H), 7.56 (dd, J=8.8, 3.1 Hz,
1H), 7.71 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.8 Hz, 1H), 8.36 (d, J=2.7
Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H) ppm. MS
(DCI/NH.sub.3): m/z 335 (M+H).sup.+. Anal. Calculated for
C.sub.20H.sub.22N.sub.4O.1.10 C.sub.7H.sub.8SO.sub.3.0.80H.sub.2O:
C, 61.81; H, 6.07; N, 10.41. Found: C, 62.15; H, 5.92; N,
10.05.
Example 58
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indoli-
n-2-one bis(hydrochloric acid)
Example 58A
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one
[0275] Under N.sub.2, 5-Bromoindolin-2-one (Aldrich, 2.11 g, 10.0
mmol) was coupled with bis(pinacolato)dibon (Frontier Scientific,
3.05 g, 12 mmol) in the presence of KOAc (Aldrich, 1.50 g, 15.0
mmol) under the catalysis of PdCl.sub.2(dppf).
CH.sub.2Cl.sub.2(Aldrich, 163 mg, 0.2 mmol) in anhydrous dioxane
(Aldrich, 50 mL) at 85.degree. C. for 15 hours. After the reaction
was completed, it was cooled down to ambient temperature and
diluted with EtOAc (100 mL). The mixture was then washed with brine
(2.times.10 mL) and concentrated. The residue was purified with
chromatography on silica gel (EtOAc/hexanes, v. 1:1, R.sub.f=0.5)
to provide the title compound (2.43 g, yield, 93.8%). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.24 (s, 12H), 3.51 (s, 2H), 6.88 (d,
J=8.5 Hz, 1H), 7.52-7.75 (m, 2H) ppm. MS (DCI/NH.sub.3): m/z 260
(M+H).sup.+.
Example 58B
5-{5[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indolin-
-2-one
[0276] The product of Example 9A (200 mg, 0.80 mmol), was coupled
with the product of Example 58A (260 mg, 1.0 mmol) according to the
procedure of Example 9B. to provide the title compound (130 mg,
yield, 46.4%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.93-2.04
(m, 2H), 2.06-2.15 (m, J=2.4 Hz, 4H), 2.14-2.25 (m, 2H), 2.33 (s,
3H), 3.20 [s (broad), 2H], 4.67 (t, J=5.1 Hz, 1H), 6.96 (d, J=8.1
Hz, 1H), 7.38 (dd, J=8.8, 3.1 Hz, 1H), 7.69-7.80 (m, 3H), 8.18 (d,
J=3.1 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 350 (M+H).sup.+.
Example 58C
5-{5-[(endo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indoli-
n-2-one bis(hydrochloric acid)
[0277] The product of Example 48A (80 mg, 0.24 mmol) was treated
with ptoluenesulfonic acid monohydrate TsOH.H.sub.20 (Aldrich, 57
mg, 0.3 mmol) in EtOAc/EtOH (v. 4:1, 10 mL) at ambient temperature
for 10 hours. The precipitated solid was filtered and dried to
provide the title compound (100 mg, yield, 79.6%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 2.31-2.67 (m, 8H), 2.85 (s, 3H), 3.68 (s,
2H), 3.90-4.08 (m, 2H), 5.03 (t, J=4.6 Hz, 1H), 7.14 (d, J=9.2 Hz,
1H), 7.73-7.82 (m, 2H), 8.22-8.34 (m, 2H), 8.53 (d, J=2.4 Hz, 1H)
ppm. MS (DCI/NH.sub.3) m/z 350 (M+H).sup.+. Anal. Calculated for
C.sub.21H.sub.23N.sub.3O.sub.2.2.00 HCl.3.0H.sub.2O: C, 52.95; H,
6.56; N, 8.82. Found: C, 52.67; H, 6.47; N, 8.62.
Example 59
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
bis(hydrochloric acid
Example 59A
(endo)-3-(6-Chloropyridin-3-yloxy)-8-azabicyclo[3.2.1]octane
[0278] To a solution of the product of Example 9A (253 mg, 1.0
mmol) in anhydrous 1,2-dichloroethane (Aldrich, 10 mL) was added
1-chloroethyl carbonochloridate (Aldrich, 286 mg, 2.0 mmol). The
mixture was heated to reflux for 15 hours. It was then
concentrated, the residue was diluted with 5 mL of methanol. The
solution was stirred at 65.degree. C. for 1 h. and then
concentrated. The residue was purified with chromatography on
silica gel (CH.sub.2Cl.sub.2:MeOH:NH.sub.3.H.sub.2O, v. 90:10:2,
R.sub.f=0.1) to give the title compound (180 mg, yield, 75%).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.03-2.62 (m, 8H),
4.01-4.14 (m, 2H), 4.75-4.82 (m, 1H), 7.37-7.42 (m, 1H), 7.44 (d,
J=3.1 Hz, 1H), 8.03-8.13 (m, 1H) ppm. MS (DCI/NH.sub.3) m/z 241
(M+H).sup.+, 239 (M+H).sup.+.
Example 59B
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
[0279] The product of Example 59A (180 mg, 0.75 mmol), was coupled
with 1H-indol-5-ylboronic acid (160 mg, 1.0 mmol) according to the
procedure of Example 9B. to provide the title compound (120 mg,
yield, 50.1%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.77-1.94
(m, 2H), 1.96-2.07 (m, 2H), 2.07-2.30 (m, 4H), 3.46-3.59 (m, 2H),
4.73 (t, J=4.9 Hz, 1H), 6.51 (d, J=4.1 Hz, 1H), 7.26 (d, J=3.1 Hz,
1H), 7.39 (dd, J=8.8, 3.1 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.62
(dd, J=8.5, 1.7 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 8.03 (d, J=1.7 Hz,
1H), 8.17 (d, J=2.7 Hz, 1H) ppm. MS (DCI/NH.sub.3) m/z 320
(M+H).sup.+.
Example 59C
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
bis(hydrochloric acid
[0280] The product of Example 59B (120 mg, 0.38 mmol) was treated
with HCl (4 M, in dioxane, 0.2 mL, 0.8 mmol) in EtOAc (5.0 mL) at
ambient temperature for 10 hours. The precipitated solid was
filtered and dried to provide the title compound (130 mg, yield,
79.6%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.09-2.26 (m,
2H), 2.28-2.43 (m, 2H), 2.40-2.59 (m, 4H), 4.02-4.23 (m, 2H), 5.02
(t, J=4.4 Hz, 1H), 6.65 (d, J=3.1 Hz, 1H), 7.42 (d, J=3.4 Hz, 1H),
7.57-7.71 (m, 2H), 8.15 (s, 1H), 8.19 (dd, J=9.1, 2.7 Hz, 1H), 8.29
(d, J=9.1 Hz, 1H), 8.44 (d, J=2.7 Hz, 1H) ppm. MS (DCI/NH.sub.3)
m/z 320 (M+H).sup.+. Anal. Calculated for
C.sub.20H.sub.21N.sub.3O.2.00 HCl.1.18H.sub.2O: C, 58.08; H, 6.18;
N, 10.16. Found: C, 57.73; H, 6.37; N, 9.95.
Example 60
(1R,3r,5S,8s)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabicyclo[3-
.2.1]octane 8-oxide
[0281] 3-Chlorobenzoperoxoic acid (Aldrich, 70-75%, 240 mg, 1.0
mmol) was added to a solution of product of Example 9B (333 mg, 1.0
mmol) in MeOH (10 mL). It was then stirred at ambient temperature
for 4 hours. The solution was directly purified by preparative HPLC
[Gilson, column, Xterra.RTM. 5 .mu.m, 40.times.100 mm. Eluting
Solvent, MeCN/H.sub.2O (0.1 M aqueous ammonium bicarbonate,
adjusted to pH 10 with ammonium hydroxide) (v.10/90 to 75/25 over
20 minutes, Flow rate of 40 mL/minute, uv detector set to 250 nm].
The fractions with lower rention time were collected and
concentrated under reduced pressure to provide the title compound
(130 mg, yield, 37.2%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
2.19-2.42 (m, 4H), 2.45-2.74 (m, 4H), 3.34 (s, 3H), 3.57-3.70 (m,
2H), 4.72 (t, J=5.3 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 7.27 (d, J=3.1
Hz, 1H), 7.40-7.52 (m, 2H), 7.64 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (d,
J=8.8 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 8.23 (d, J=3.1 Hz, 1H) ppm;
MS (DCI/NH.sub.3) m/z 350 (M+H).sup.+.
Example 61
(1R,3r,5S,8r)-3-(6-(1H-Indol-5-yl)pyridin-3-yloxy)-8-methyl-8-azabicyclo[3-
.2.1]octane 8-oxide
[0282] 3-Chlorobenzoperoxoic acid (Aldrich, 70-75%, 240 mg, 1.0
mmol) was added to a solution of product of Example 9B (333 mg, 1.0
mmol) in MeOH (10 mL). It was then stirred at ambient temperature
for 4 hours. The solution was directly purified by preparative HPLC
[Gilson, column, XterraB 5 pm, 40.times.100 mm. Eluting Solvent,
MeCN/H.sub.2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH
10 with ammonium hydroxide) (v. 10/90 to 75/25 over 20 minutes,
Flow rate of 40 mL/minute, uv detector set to 250 nm]. The
fractions with higher rention time were collected and concentrated
under reduced pressure to provide the title compound (1 10 mg,
yield, 3 1.5%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.96-2.07
(m, 2H), 2.19-2.37 (m, 2H), 2.44-2.59 (m, 2H), 3.06 (dt, J=15.3,
4.2 Hz, 2H), 3.24 (s, 3H), 3.47-3.59 (m, 2H), 4.71-4.81 (m, 1H),
6.52 (d, J=3.1 Hz, 1H), 7.27 (d, J=3.4 Hz, 1H), 7.42-7.50 (m, 2H),
7.64 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 8.05 (d,
J=1.7 Hz, 1H), 8.24 (d, J=3.1 Hz, 1H) ppm; MS (DCI/NH.sub.3) m/z
350 (M+H).sup.+.
Example 62
4-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
trifluoroacetate
[0283] The product of Example 59A (120 mg, 0.50 mmol), was coupled
with 1H-indol-4-ylboronic acid (Frontier, 121 mg, 0.75 mmol)
according to the procedure of Example 9B. The crude mixture was
purified with preparative HPLC (Gilson, column, Xterra.RTM. 5
.mu.m, 40.times.100 mm. Eluting Solvent, MeCN/H.sub.2O containing
0.1% v. TFA (90% to 10% over 25 minutes, Flow rate of 40 mL/minute,
uv detector set to 254 nm). The fractions containing the desired
product were collected and concentrated under reduced pressure and
the residue was stirred in ether/ethanol (v. 10/1, 5 mL) at ambient
temperature for 16 hours to provide the title compound. (80 mg,
yield, 29.2%). NMR (300 MHz, CD.sub.3OD) .delta. 2.06-2.24 (m, 2H),
2.25-2.60 (m, 6H), 4.00-4.33 (m, 2H), 4.90-5.02 (m, 1H), 6.72 (dd,
J=3.39, 1.02 Hz, 1H), 7.25-7.32 (m, 1H), 7.34-7.39 (m, 1H), 7.43
(d, J=3.05 Hz, 1H), 7.58 (dt, J=7.80, 1.02 Hz, 1H), 7.93 (dd,
J=8.99, 2.88 Hz, 1H), 8.11 (d, J=8.82 Hz, 1H), 8.46 (d, J=2.71 Hz,
1H) ppm. MS (DCI/NH.sub.3) m/z 320 (M+H).sup.+. Anal. Calc. for
C.sub.20H.sub.21N.sub.3O.2.00CF.sub.3CO.sub.2H.0.50H.sub.2O: C,
51.80; H, 4.35; N, 7.55. Found: C, 51.84; H, 4.28; N, 7.30.
Example 63
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
bis(hydrochloric acid
Example 63A
(exo)-3-(6-Chloropyridin-3-yloxy)-8-azabicyclo[3.2.1]octane
[0284] To a solution of the product of Example 11A (2.52 g, 9.97
mmol) in 1,2-dichloroethane (25 ml) (anhydrous) was added
1-chloroethyl carbonochloridate (5.54 ml, 49.9 mmol). The mixture
was then heated to 100.degree. C. for 50 h. It was then cooled down
to ambient temperature, 25 mL of MeOH was added. The mixture was
then heated to reflux for 1 hour. It is concentrated and the crude
was purified with chromatography on silica gel
(CH.sub.2Cl.sub.2:MeOH:NH.sub.3H.sub.2O, v. 90:10:2, R.sub.f=0.15)
to give the title compound (180 mg, yield, 75%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.56-1.71 (m, 2H), 1.74-1.94 (m, 4H),
2.01-2.26 (m, 2H), 3.46-3.73 (m, 2H), 4.58-4.76 (m, 1H), 7.32 (d,
J=8.1 Hz, 1H), 7.43 (dd, J=8.8, 3.0 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H)
ppm. MS (DCI/NH.sub.3) m/z 241 (M+H).sup.+, 239 (M+H).sup.+.
Example 63B
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
[0285] The product of Example 63A (0.24 g, 1.0 mmol) was coupled
with 1H-indol-5-ylboronic acid (Frontier, 0.241 g, 1.50 mmol)
according to the procedure of Example 9B to provide the title
compound (0.25 g, yield, 79%). .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.69-1.83 (m, 2H), 1.86-1.99 (m, 4H), 2.1.8-2.32 (m, 2H),
3.67-3.87 (m, 2H), 4.69-4.82 (m, 1H), 6.52 (d, J=2.37 Hz, 1H), 7.27
(d, J=3.05 Hz, 1H), 7.45 (dt, J=8.48, 0.85 Hz, 1H), 7.49 (dd,
J=8.82, 3.05 Hz, 2H), 7.62 (dd, J=8.48, 1.70 Hz, 2H), 7.76 (d,
J=8.14 Hz, 2H), 8.03 (d, J=1.36 Hz, 2H), 8.22 (d, J=2.37 Hz, 1H)
ppm; MS (DCI/NH.sub.3) m/z 320 (M+H).sub.+.
Example 63C
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole
bis(hydrochloric acid)
[0286] The product of Example 63B (0.25 g, 0.79 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) in EtOAc/EtOH
(v. 10/1, 10 mL). The precipitated solid was filtered and dried to
give the title compound (0.20 g, yield, 64.9%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta.1.94-2.13 (m, 2H), 2.12-2.35 (m, 4H),
2.42-2.68 (m, 2H), 4.09-4.37 (m, 2H), 5.05-5.28 (m, 1H), 6.67 (d,
J=3.39 Hz, 1H), 7.43 (d, J=3.05 Hz, 1H), 7.57-7.72 (m, 2H), 8.16
(s, 1H), 8.27-8.39 (m, 2H), 8.52 (d, J=2.37 Hz, 1H) ppm; MS
(DCI/NH.sub.3) m/z 320 (M+H).sup.+. Anal. Calc. for
C.sub.20H.sub.21N.sub.3O.2.00HCl.0.90H.sub.2O: C, 58.80; H, 6.12;
N, 10.29. Found: C, 58.50; H, 5.86; N, 10.08.
Example 64
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}indolin-2-one
[0287] The product of Example 59A (119 mg, 0.50 mmol), was coupled
with the product of Example 58A (194 mg, 0.75 mmol) according to
the procedure of Example 9B to provide the title compound (150 mg,
yield, 89.0%). .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
1.86-2.42 (m, 8H), 3.54 (s, 2H), 3.89-4.06 (m, 2H), 4.83 (t, J=4.07
Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.47 (dd, J=8.82, 3.05 Hz, 1H),
7.78-7.94 (m, 3H), 8.32 (d, J=2.71 Hz, 1H), 10.50 (s, 1H) ppm; MS
(DCI/NH.sub.3) m/z 336 (M+H).sup.+.
Example 65
5-{5-[(endo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3-
-b]pyridine
[0288] The product of Example 59A (200 mg, 0.80 mmol), was coupled
with the product of Example 47A (183 mg, 0.75 mmol) according to
the procedure of Example 9B to provide the title compound (80 mg,
yield, 49.9%). .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
1.89-2.16 (m, 4H), 2.17-2.40 (m, 4H), 3.78-4.26 (m, 2H), 4.86 (t,
J=4.24 Hz, 1H), 6.51 (dd, J=3.39, 1.70 Hz, 1H), 7.46-7.58 (m, 2H),
7.97 (d, J=8.82 Hz, 1H), 8.39 (d, J=2.71 Hz, 1H), 8.52 (d, J=2.03
Hz, 1H), 8.88 (d, J=2.03 Hz, 1H), 11.70 (s, 1H) ppm; MS
(DCI/NH.sub.3) m/z 321 (M+H).sup.+.
Example 66
5-{5-[(exo)-8-Azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-pyrrolo[2,3--
b]pyridine
[0289] The product of Example 63A (200 mg, 0.80 mmol) was coupled
with the product of Example 47A (183 mg, 0.75 mmol) according to
the procedure of Example 9B to provide the title compound (120 mg,
yield, 74.9%). .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
1.82-2.18 (m, 6H), 2.18-2.40 (m, 2H), 3.91-4.30 (m, 2H), 4.71-5.30
(m, 1H), 6.51 (dd, J=3.39, 1.70 Hz, 1H), 7.47-7.55 (m, 1H), 7.61
(dd, J=8.82, 3.05 Hz, 1H), 7.94 (d, J=8.82 Hz, 1H), 8.42 (d, J=2.71
Hz, 1H), 8.52 (d, J=2.03 Hz, 1H), 8.88 (d, J=2.03 Hz, 1H), 11.71
(s, 1H) ppm; MS (DCI/NH.sub.3) m/z 321 (M+H).sup.+.
Compositions of the Invention
[0290] The invention also provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
formula (I) in combination with a pharmaceutically acceptable
carrier. The compositions comprise compounds of the invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions can be
formulated for oral administration in solid or liquid form, for
parenteral injection or for rectal administration.
[0291] The term "pharmaceutically acceptable carrier," as used
herein, means a nontoxic, inert solid, semi-solid or liquid filler,
diluent, encapsulating material or formulation auxiliary of any
type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other nontoxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
[0292] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration, including intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous,
intraarticular injection and infusion.
[0293] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof. Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0294] These compositions can also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. 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 also can 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
monostearate and gelatin.
[0295] In some cases, in order to prolong the effect of a drug, it
is often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug can depend upon its rate of dissolution, which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
dissolving or suspending the drug in an oil vehicle can administer
a parenterally administered drug form.
[0296] Suspensions, in addition to the active compounds, can
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0297] If desired, and for more effective distribution, the
compounds of the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
[0298] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0299] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0300] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation also can be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that can
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0301] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0302] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
[0303] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They can optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples
of materials useful for delaying release of the active agent can
include polymeric substances and waxes.
[0304] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable nonirritating carriers
such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0305] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0306] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0307] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
[0308] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0309] Powders and sprays can contain, in addition to the compounds
of this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
[0310] Compounds of the invention also can be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0311] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y., (1976), p. 33 et seq.
[0312] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants. Ophthalmic formulations, eye ointments,
powders and solutions are also contemplated as being within the
scope of this invention. Aqueous liquid compositions of the
invention also are particularly useful.
[0313] The compounds of the invention can be used in the form of
pharmaceutically acceptable salts, esters, or amides derived from
inorganic or organic acids. The term "pharmaceutically acceptable
salts, esters and amides," as used herein, include salts,
zwitterions, esters and amides of compounds of formula (I) which
are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response, and the like, are
commensurate with a reasonable benefitfrisk ratio, and are
effective for their intended use.
[0314] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well-known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
[0315] Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, fumarate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),
lactate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate.
[0316] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0317] Examples of acids which can be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid, and citric acid.
[0318] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium, and aluminum salts, and the like,
and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the such as. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
[0319] The term "pharmaceutically acceptable ester," as used
herein, refers to esters of compounds of the invention which
hydrolyze in vivo and include those that break down readily in the
human body to leave the parent compound or a salt thereof. Examples
of pharmaceutically acceptable, non-toxic esters of the invention
include C.sub.1-to-C.sub.6 alkyl esters and C.sub.5-to-C.sub.7
cycloalkyl esters, although C.sub.1-to-C.sub.4 alkyl esters are
preferred. Esters of the compounds of formula (I) can be prepared
according to conventional methods. Pharmaceutically acceptable
esters can be appended onto hydroxy groups by reaction of the
compound that contains the hydroxy group with acid and an
alkylcarboxylic acid such as acetic acid, or with acid and an
arylcarboxylic acid such as benzoic acid. In the case of compounds
containing carboxylic acid groups, the pharmaceutically acceptable
esters are prepared from compounds containing the carboxylic acid
groups by reaction of the compound with base such as triethylamine
and an alkyl halide, alkyl trifilate, for example with methyl
iodide, benzyl iodide, cyclopentyl iodide. They also can be
prepared by reaction of the compound with an acid such as
hydrochloric acid and an alkylcarboxylic acid such as acetic acid,
or with acid and an arylcarboxylic acid such as benzoic acid.
[0320] The term "pharmaceutically acceptable amide," as used
herein, refers to non-toxic amides of the invention derived from
ammonia, primary C.sub.1-to-C.sub.6 alkyl amines and secondary
C.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,
the amine can also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2
dialkyl secondary amides are preferred. Amides of the compounds of
formula (I) can be prepared according to conventional methods.
Pharmaceutically acceptable amides can be prepared from compounds
containing primary or secondary amine groups by reaction of the
compound that contains the amino group with an alkyl anhydride,
aryl anhydride, acyl halide, or aroyl halide. In the case of
compounds containing carboxylic acid groups, the pharmaceutically
acceptable esters are prepared from compounds containing the
carboxylic acid groups by reaction of the compound with base such
as triethylamine, a dehydrating agent such as dicyclohexyl
carbodiimide or carbonyl diimidazole, and an alkyl amine,
dialkylamine, for example with methylamine, diethylamine,
piperidine. They also can be prepared by reaction of the compound
with an acid such as sulfuric acid and an alkylcarboxylic acid such
as acetic acid, or with acid and an arylcarboxylic acid such as
benzoic acid under dehydrating conditions as with molecular sieves
added. The composition can contain a compound of the invention in
the form of a pharmaceutically acceptable prodrug.
[0321] The term "pharmaceutically acceptable prodrug" or "prodrug,"
as used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use. Prodrugs of the invention can be
rapidly transformed in vivo to a parent compound of formula (I),
for example, by hydrolysis in blood. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.
Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987).
[0322] The invention contemplates pharmaceutically active compounds
either chemically synthesized or formed by in vivo
biotransformation to compounds of formula (I).
Determination of Biological Activity
[0323] To determine the effectiveness of representative compounds
of this invention as .alpha.7 nAChRs, the compounds of the
invention were evaluated according to the [.sup.3H]-DPPB binding or
the [.sup.3H]-methyllycaconitin (MLA) binding assay (both measures
of .alpha.7 NNR binding) and considering the [.sup.3H]-cytisine
binding assay (measure of .alpha.4.beta.2 interactions), which were
performed as described below.
[.sup.3H]-Cytisine Binding
[0324] Binding conditions were modified from the procedures
described in Pabreza L A, Dhawan, S, Kellar K J, [.sup.3H]-Cytisine
Binding to Nicotinic Cholinergic Receptors in Brain, Mol. Pharm.
39: 9-12, 1991. Membrane enriched fractions from rat brain minus
cerebellum (ABS Inc., Wilmington, Del.) were slowly thawed at
4.degree. C., washed and resuspended in 30 volumes of BSS-Tris
buffer (120 mM NaClf5 mM KCl 12 mM CaCl.sub.2/2 mM MgCl.sub.2/50 mM
Tris-Cl, pH 7.4, 4.degree. C.). Samples containing 100-200 pg of
protein and 0.75 nM [3H]-cytisine (30 C.sub.i/mmol; Perkin
ElmerfNEN Life Science Products, Boston, Mass.) were incubated in a
final volume of 500 .mu.L for 75 minutes at 4.degree. C. Seven
log-dilution concentrations of each compound were tested in
duplicate. Non-specific binding was determined in the presence of
10 .mu.M (-)-nicotine. Bound radioactivity was isolated by, vacuum
filtration onto prewetted glass fiber filter plates (Millipore,
Bedford, Mass.) using a 96-well filtration apparatus (Packard
Instruments, Meriden, Conn.) and were then rapidly rinsed with 2 mL
of ice-cold BSS buffer (120 mM NaCl 15 mM KCl 12 mM CaCl.sub.2/2 mM
MgCl.sub.2). Packard MicroScint-20.RTM.-scintillation cocktail (40
.mu.L) was added to each well and radioactivity determined using a
Packard TopCount.RTM. instrument. The IC.sub.50 values were
determined by nonlinear regression in Microsoft Excel.RTM.
software. K.sub.i values were calculated from the IC.sub.50s using
the Cheng-Prusoff equation, where
K.sub.i=IC.sub.50/1+[Ligand]/K.sub.D].
[.sup.3H]-Methyllycaconitine (MLA) Binding
[0325] Binding conditions were similar to those for [3H]-cytisine
binding. Membrane enriched fractions from rat brain minus
cerebellum (ABS Inc., Wilmington, Del.) were slowly thawed at
4.degree. C., washed and resuspended in 30 volumes of BSS-Tris
buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl.sub.2, 2 mM MgCl.sub.2,
and 50 mM Tris-Cl, pH 7.4, 22.degree. C.). Samples containing
100-200 .mu.g of protein, 5 nM [3H]-MLA (25 C.sub.i/mmol; Perkin
Elmer/NEN Life Science Products, Boston, Mass.) and 0.1% bovine
serum albumin (BSA, Millipore, Bedford, Mass.) were incubated in a
final volume of 500 .mu.L for 60 minutes at 22.degree. C. Seven
log-dilution concentrations of each compound were tested in
duplicate. Nonspecific binding was determined in the presence of 10
.mu.M MLA. Bound radioactivity was isolated by vacuum filtration
onto glass fiber filter plates prewetted with 2% BSA using a
96-well filtration apparatus (Packard Instruments, Meriden, Conn.)
and were then rapidly rinsed with 2 mL of ice-cold BSS. Packard
MicroScint-20.RTM. scintillation cocktail (40 pL) was added to each
well and radioactivity was determined using a Packard TopCount.RTM.
instrument. The IC.sub.50 values were determined by nonlinear
regression in Microsoft Excel.RTM. software. K.sub.i values were
calculated from the IC.sub.50s using the Cheng-Prusoff equation,
where K.sub.i=IC.sub.50/1+[Ligand]/K.sub.D].
[.sup.3H]-DPPB Binding
[0326] [.sup.3H]-DPPB,
[.sup.3H]-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide, binding to the .alpha.7 nAChR subtype
was determined using membrane enriched fractions from rat brain
minus cerebellum or human cortex (ABS Inc., Wilmington, Del.).
Pellets were thawed at 4.degree. C., washed and resuspended with a
Polytron at a setting of 7 in 30 volumes of BSS-Tris buffer (120 mM
NaCl, 5 mM KCl, 2 mM CaCl.sub.2, 2 mM MgCl.sub.2, and 50 mM
Tris-Cl, pH 7.4, 4.degree. C.). Seven log-dilution concentrations
of test compounds containing 100-200 .mu.g of protein, and 0.5 nM
[.sup.3H]-DPPB (62.8 Ci/mmol; R46V, Abbott Labs) were incubated in
a final volume of 500 .mu.l for 75 minutes at 4.degree. C. in
duplicate. Non-specific binding was determined in the presence of
10 .mu.M methyllycaconitine. Bound radioactivity was collected on
Millipore MultiScreen.RTM. harvest plates FB presoaked with 0.3%
PEI using a Packard cell harvester, washed with 2.5 ml ice-cold
buffer, and radioactivity was determined using a Packard TopCount
Microplate beta counter. IC.sub.50 values were determined by
nonlinear regression in Microsoft.RTM. Excel or Assay Explorer.
K.sub.i values were calculated from the IC.sub.50s using the
Cheng-Prusoff equation, where
K.sub.i=IC.sub.50/1+[Ligand]/K.sub.D[.sup.3H] was obtained
according to the preparation procedures described below.
[Methyl-.sup.3H]2,2-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide Preparation
[0327]
[Methyl-.sup.3]2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azo-
nia-bicyclo[2.2.1]heptane; iodide used in the [.sup.3H]-DPPB
binding assay above was prepared according to the following
procedures.
Step 1: Preparation of t-Butyl
(S,S)-5-(6-Phenyl-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbo-
xylate
[0328] Triethylamine (20 mL) was added to a suspension of t-butyl
(S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.43 g, 17.3
mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine
(3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL)
and the mixture was heated under nitrogen at 100.degree. C. for 7
days. The dark mixture was cooled to room temperature, and the
resulting precipitate was isolated by filtration, washed with
toluene (15 mL) and dried under vacuum to provide the title
compound as an off-white solid (3.00 g). The filtrate was
concentrated and the residue wa purified by column chromatography
on silica gel, eluting with ethyl acetate, to provide additional
product (0.41 g, total yield 3.41 g, 56%): MS (DCI/NH3) m/z 353
(M+H)+.
Step 2: Preparation of (S,S)-2-Methyl
5-(6-phenyl-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane
[0329] The product obtained from Step 1 (3.41 g, 9.7 mmol) was
dissolved in formic acid (20 mL) and treated with formalin (37% by
weight, 1 .O g, 12.3 mmol). The mixture was heated at 100.degree.
C. for 1 h, and the brown solution was cooled to room temperature
and concentrated under vacuum. The residue was purified by column
chromatography on silica gel, eluting with CH2Cl2-CH3OH--NH4OH
(95:5:1) to provide the title compound as an off-white solid (2.50
g, 96%): MS (DCI/NH3) m/z 267 (M+H)+.
Step 3: Preparation of
[.sup.3H]-(S,S)-2,2-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide ([.sup.3H]-DPPB)
[0330] [.sup.3H]Methyl iodide in toluene (250 mCi in 0.1 mL,
85Ci/mmol, American Radiolabeled Chemicals, Inc.) was combined with
a solution of the product obtained from Step 2 in dichloromethane
(0.788 mg, 2.96 mmole in 0.45 mL). The vial was capped and the
mixture was allowed to react overnight at room temperature.
Methanol was added and the solvents were evaporated to give 42 mCi.
The product was taken up in methanol for HPLC purification.
Step 4: Purification by High Performance Liquid Chromatography
(HPLC)
[0331] About 7 mCi of [.sup.3H]was evaporated to dryness and the
residue was dissolved in total about 4.5 ml acetonitrile:water:TFA
(15:85:0.1). Approximately 0.9 mL per injection were made onto a
Phenomenex Luna C18(2) column (5 micron, 250 mm.times.4.6 mm ID)
using an Agilent HPLC system. [3H]-DPPB was eluted by a gradient
mobile phase from 10% B to 20% B in 20 min where Mobile Phase
A=0.1% trifluoroacetic acid in water and Mobile Phase B=0.1%
trifluoroacetic acid in acetonitrile at a flow rate of
approximately 1 mL/min. Peak detection and chromatograms were
obtained with an Agilent variable wavelength UV detector set at 275
nm. The fractions containing [3H]-DPPB were collected at
approximately 14 minutes using an Agilent fraction collector. The
fractions were combined and the solvents were evaporated in vacuo.
The residue was dissolved in 200 proof ethanol (2 mL) to give 0.7
mCi.
Step 5: Determination of Purity and Specific Activity
[0332] [.sup.3H]-DPPB was assayed using an Agilent 1100 series HPLC
system consisting of a quaternary pump, an autosampler, and a
photodiode array UV detector. A Packard Radiomatic A 500
radioactivity detector was connected to the HPLC system. For
radiodetection, a 500 mL flow cell and a 3:1 ratio of Ultima-Flo M
scintillation cocktail to HPLC mobile phase were used. The analyses
were performed using a Phenomenex Luna.sup.18(2) column (5 microns,
250 mm.times.4.6 mm ID). The mobile phase consisted of a gradient
starting with 10% B and ramping to 20% B in 20 minutes followed by
ramping to 90% B in 1 minute and hold at 90% B for 9 minutes, where
Mobile Phase A=0.1% trifluoroacetic acid in water and Mobile Phase
B=0.1% trifluoroacetic acid in acetonitrile. The flow rate was set
at approximately 1 mL/min and the UV detection was set at 275
nm.
[0333] The radiochemical purity of [.sup.3H]was found to be
>9.about.8%. The specific activity was determined to be 62.78
Ci/mmol by mass spectroscopy.
[0334] Compounds of the invention had K.sub.i values of from about
1 nanomolar to about 10 micromolar when tested by the [.sup.3H]-MLA
assay, many having a K.sub.i of less than 1 micromolar.
[.sup.3H]-Cystine binding values of compounds of the invention
ranged from about 1 nanomolar to at least 100 micromolar.
Alternatively, the K.sub.i value as measured by [.sup.3H]-DPPB
assay can be used in place of the K.sub.i MLA.
Methods of the Invention
[0335] Compounds and compositions of the invention are useful for
modulating the effects of nAChRs, and more particularly .alpha.7
nAChRs. In particular, the compounds and compositions of the
invention can be used for treating and preventing disorders
modulated by .alpha.7 nAChRs. Typically, such disorders can be
ameliorated by selectively modulating the .alpha.7 nAChRs in a
mammal, preferably by administering a compound or composition of
the invention, either alone or in combination with another active
agent, for example, as part of a therapeutic regimen. Also, some
compounds of the invention possess affinity at the .alpha.4 .beta.2
nAChRs in addition to .alpha.7 nAChRs, and selective compounds with
dual affinities at both receptor subtypes also are expected to have
beneficial effects. The compounds of the invention, including but
not limited to those specified in the examples, possess an affinity
for nAChRs, and more particularly .alpha.7 nAChRs. As .alpha.7
nAChRs ligands, the compounds of the invention can be useful for
the treatment and prevention of a number of .alpha.7 nAChR-mediated
diseases or conditions.
[0336] For example, .alpha.7 nAChRs have been shown to play a
significant role in enhancing cognitive function, including aspects
of learning, memory and attention (Levin, E. D., J. Neurobiol. 53:
633-640, 2002). As such, .alpha.7 ligands are suitable for the
treatment of cognitive disorders including, for example, attention
deficit disorder, attention deficit hyperactivity disorder (ADHD),
Alzheimer's disease (AD), mild cognitive impairment, senile
dementia, AIDS dementia, Pick's Disease, dementia associated with
Lewy bodies, and dementia associated with Down's syndrome, as well
as cognitive deficits associated with schizophrenia.
[0337] In addition, .alpha.7-containing nAChRs have been shown to
be involved in the neuroprotective effects of nicotine both in
vitro (Jonnala, R. B. and Buccafusco, J. J., J. Neurosci. Res. 66:
565-572, 2001) and in vivo (Shimohama, S. et al., Brain Res. 779:
359-363, 1998). More particularly, neurodegeneration underlies
several progressive CNS disorders, including, but not limited to,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, dementia with Lewy bodies, as well
as diminished CNS function resulting from traumatic brain injury.
For example, the impaired function of .alpha.7 nAChRs by P-amyloid
peptides linked to Alzheimer's disease has been implicated as a key
factor in development of the cognitive deficits associated with the
disease (Liu, Q.-S., Kawai, H., Berg, D. K., PNAS 98: 4734-4739,
2001). The activation of .alpha.7 nAChRs has been shown to block
this neurotoxicity (Kihara, T. et al., J. Biol. Chem. 276:
13541-13546, 2001). As such, selective ligands that enhance
.alpha.7 activity can counter the deficits of Alzheimer's and other
neurodegenerative diseases. Schizophrenia is a complex disease that
is characterized by abnormalities in perception, cognition, and
emotions. Significant evidence implicates the involvement of
.alpha.7 nAChRs in this disease, including a measured deficit of
these receptors in postmortem patients (Leonard, S. Eur. J.
Pharmacol. 393: 237-242, 2000). Deficits in sensory processing
(gating) are one of the hallmarks of schizophrenia. These deficits
can be normalized by nicotinic ligands that operate at the .alpha.7
nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189-202, 1998;
Stevens, K. E. et al., Psychopharmacology 136: 320-327, 1998).
Thus, .alpha.7 ligands demonstrate potential in the treatment
schizophrenia. Angiogenesis, a process involved in the growth of
new blood vessels, is important in beneficial systemic functions,
such as wound healing, vascularization of skin grafts, and
enhancement of circulation, for example, increased circulation
around a vascular occlusion. Non-selective nAChR agonists like
nicotine have been shown to stimulate angiogenesis (Heeschen, C. et
al., Nature Medicine 7: 833-839, 2001). Improved angiogenesis has
been shown to involve activation of the .alpha.7 nAChR (Heeschen,
C. et al, J. Clin. Invest. 110: 527-536, 2002). Therefore, nAChR
ligands that are selective for the .alpha.7 subtype offer improved
potential for stimulating angiogenesis with an improved side effect
profile.
[0338] A population of .alpha.7 nAChRs in the spinal cord modulate
serotonergic transmission that have been associated with the
pain-relieving effects of nicotinic compounds (Cordero-Erausquin,
M. and Changeux, J.-P. PNAS 98:2803-2807, 2001). The .alpha.7 nAChR
ligands demonstrate therapeutic potential for the treatment of pain
states, including acute pain, post-surgical pain, as well as
chronic pain states including inflammatory pain and neuropathic
pain. Moreover, .alpha.7 nAChRs are expressed on the surface of
primary macrophages that are involved in the inflammation response,
and that activation of the .alpha.7 receptor inhibits release of
TNF and other cytokines that trigger the inflammation response
(Wang, H. et al Nature 421: 384-388, 2003). Therefore, selective
.alpha.7 ligands demonstrate potential for treating conditions
involving TNF-mediated diseases, for example, rheumatoid arthritis,
Crohn's disease, ulcerative colitis, inflammatory bowel disease,
organ transplant rejection, acute immune disease associated with
organ transplantation, chronic immune disease associated with organ
transplantation, septic shock, toxic shock syndrome, sepsis
syndrome, depression, and rheumatoid spondylitis.
[0339] The mammalian sperm acrosome reaction is an exocytosis
process important in fertilization of the ovum by sperm. Activation
of an .alpha.7 nAChR on the sperm cell has been shown to be
essential for the acrosome reaction (Son, J.-H. and Meizel, S.
Biol. Reproduct. 68: 1348-1353 2003). Consequently, selective
.alpha.7 agents demonstrate utility for treating fertility
disorders.
[0340] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting
cognition, neurodegeneration, and schizophrenia.
[0341] Cognitive impairment associated with schizophrenia often
limits the ability of patients to function normally, a symptom not
adequately treated by commonly available treatments, for example,
treatment with an atypical antipsychotic. (Rowley, M. et al., J.
Med. Chem. 44: 477-501, 2001). Such cognitive deficit has been
linked to dysfunction of the nicotinic cholinergic system, in
particular with decreased activity at .alpha.7 receptors.
[0342] (Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 002).
Thus, activators of .alpha.7 receptors can provide useful treatment
for enhancing cognitive function in schizophrenic patients who are
being treated with atypical antipsychotics. Accordingly, the
combination of an .alpha.7 nAChR ligand and an atypical
antipsychotic would offer improved therapeutic utility. Specific
examples of suitable atypical antipsychotics include, but are not
limited to, clozapine, risperidone, olanzapine, quietapine,
ziprasidone, zotepine, iloperidone, and the like.
[0343] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0344] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
invention can be employed in pure form or, where such forms exist,
in pharmaceutically acceptable salt, ester, amide or prodrug
form.
[0345] Alternatively, the compound can be administered as a
pharmaceutical composition containing the compound of interest in
combination with one or more pharmaceutically acceptable carriers.
The phrase "therapeutically effective amount" of the compound of
the invention means a sufficient amount of the compound to treat
disorders, at a reasonable benefit/risk ratio applicable to any
medical treatment. It will be understood, however, that the total
daily usage of the compounds and compositions of the invention will
be decided by the attending physician within the scope of sound
medical judgment.
[0346] The specific therapeutically effective dose level for any
particular patient will depend upon a variety of factors including
the disorder being treated and the severity of the disorder;
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well-known in the medical arts. For example, it is well
within the skill of the art to start doses of the compound at
levels lower than required to achieve the desired therapeutic
effect and to gradually increase the dosage until the desired
effect is achieved.
[0347] The total daily dose of the compounds of this invention
administered to a human or lower animal range from about 0.010
mg/kg body weight to about 1 g/kg body weight.
[0348] More preferable doses can be in the range of from about
0.010 mg/kg body weight to about 100 mg/kg body weight. If desired,
the effective daily dose can be divided into multiple doses for
purposes of administration. Consequently, single dose compositions
may contain such amounts or submultiples thereof to make up the
daily dose.
[0349] Compounds of the invention are .alpha.7 nAChRs ligands that
modulate function of .alpha.7 nAChRs by altering the activity of
the receptor or signaling. The compounds can be inverse agonists
that inhibit the basal activity of the receptor or antagonists that
completely block the action of receptor-activating agonists. The
compounds also can be partial agonists that partially block or
partially activate the .alpha.7 nAChR receptor or agonists that
activate the receptor. Binding to .alpha.7 receptor also trigger
key signaling processes involving various kinases and phosphatases
and protein-protein interactions that are important to effects on
memory, cytoprotection, gene transcription and disease
modification. Therefore, the administration of a therapeutically
effective amount of a compound of formula (I) to a mammal provides
a method of selectively modulating the effects of .alpha.4.beta.2,
.alpha.7, or both .alpha.4.beta.2 and .alpha.7 nicotinic
acetylcholine receptors.
[0350] Furthermore, the administration of a therapeutically
effective amount of a compound of formula (I) to a mammal provides
a method of treating or preventing a condition or disorder selected
from the group consisting of attention deficit disorder, attention
deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD),
mild cognitive impairment, senile dementia, AIDS dementia, Pick's
Disease, dementia associated with Lewy bodies, dementia associated
with Down's syndrome, amyotrophic lateral sclerosis, Huntington's
disease, diminished CNS function associated with traumatic brain
injury, acute pain, post-surgical pain, chronic pain, inflammatory
pain, neuropathic pain, infertility, need for new blood vessel
growth associated with wound healing, need for new blood vessel
growth associated with vascularization of skin grafts, and lack of
circulation, more particularly circulation around a vascular
occlusion, rheumatoid arthritis, Crohn's disease, ulcerative
colitis, inflammatory bowel disease, organ transplant rejection,
acute immune disease associated with organ transplantation, chronic
immune disease associated with organ transplantation, septic shock,
toxic shock syndrome, sepsis syndrome, depression, and rheumatoid
spondylitis. More preferred, the administration of a
therapeutically effective amount of a compound of formula (I) to a
mammal provides a method of treating cognitive disorders,
neurodegeneration, and schizophrenia. Furthermore, compounds of
formula (I) may also be administered in combination with an
atypical antipsychotic.
[0351] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
[0352] Various changes and modifications to the disclosed
embodiments will be apparent to those skilled in the art. Such
changes and modifications, including without limitation those
relating to the chemical structures, substituents, derivatives,
intermediates, syntheses, formulations, or methods of use of the
invention, may be made without departing from the spirit and scope
thereof.
* * * * *