U.S. patent application number 13/296895 was filed with the patent office on 2012-03-15 for spirocyclic azaadamantane derivatives and methods of use.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Jianguo Ji, Chih-Hung Lee, Tao Li, Michael R. Schrimpf, Kevin B. Sippy.
Application Number | 20120065219 13/296895 |
Document ID | / |
Family ID | 39133727 |
Filed Date | 2012-03-15 |
United States Patent
Application |
20120065219 |
Kind Code |
A1 |
Ji; Jianguo ; et
al. |
March 15, 2012 |
SPIROCYCLIC AZAADAMANTANE DERIVATIVES AND METHODS OF USE
Abstract
The invention relates to compounds that are spirocyclic
azaadamantane derivatives, particularly spirocyclic azaadamantanyl
ether or amine derivatives, compositions comprising such compounds,
methods of using such compounds and compositions, processes for
preparing such compounds, and intermediates obtained during such
processes.
Inventors: |
Ji; Jianguo; (Libertyville,
IL) ; Schrimpf; Michael R.; (Grayslake, IL) ;
Sippy; Kevin B.; (Antioch, IL) ; Li; Tao;
(Grayslake, IL) ; Lee; Chih-Hung; (Vernon Hills,
IL) |
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
39133727 |
Appl. No.: |
13/296895 |
Filed: |
November 15, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11943045 |
Nov 20, 2007 |
8076350 |
|
|
13296895 |
|
|
|
|
60876668 |
Dec 22, 2006 |
|
|
|
Current U.S.
Class: |
514/278 ;
546/18 |
Current CPC
Class: |
A61P 25/02 20180101;
C07D 471/18 20130101; A61P 29/00 20180101; A61P 9/00 20180101; A61P
15/08 20180101; A61P 25/14 20180101; A61P 25/34 20180101; A61P
17/02 20180101; A61P 29/02 20180101; A61P 9/10 20180101; A61P 3/10
20180101; A61P 19/02 20180101; A61P 43/00 20180101; A61P 25/18
20180101; A61P 25/28 20180101; A61P 25/00 20180101; A61P 21/00
20180101; A61P 25/04 20180101; A61P 31/18 20180101; A61P 25/24
20180101 |
Class at
Publication: |
514/278 ;
546/18 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61P 25/28 20060101 A61P025/28; A61P 25/00 20060101
A61P025/00; A61P 25/18 20060101 A61P025/18; A61P 19/02 20060101
A61P019/02; A61P 15/08 20060101 A61P015/08; A61P 9/00 20060101
A61P009/00; A61P 9/10 20060101 A61P009/10; A61P 29/00 20060101
A61P029/00; C07D 491/22 20060101 C07D491/22; A61P 25/04 20060101
A61P025/04 |
Claims
1. A compound of formula (I) ##STR00018## or a pharmaceutically
acceptable salt or prodrug thereof, wherein A is N or
N.sup.+--O.sup.-; X.sup.1 is CR.sup.x1 or N; X.sup.2 is CR.sup.x2
or N; X.sup.3 is CR.sup.x3 or N; X.sup.4 is CR.sup.x4 or N; L.sup.1
and L.sup.2 are each independently --O--, --NR.sup.b;
--R.sup.cC.dbd.O, or C.sub.1-C.sub.3 alkyl; R.sup.x1, R.sup.x2,
R.sup.x3, and R.sup.x4 are each independently H, alkyl, aryl,
cyclic alkyl, halogen, halo alkyl, heteroaryl, OR.sup.b,
NR.sup.dR.sup.e, COR.sup.b, CN, CO.sub.2R.sup.b, or
CONR.sup.dR.sup.e; R.sup.b, R.sup.d, and R.sup.e are independently
H, alkyl, aryl, alkylcarbonyl, alkoxylcarbonyl, or heteroaryl; and
R.sup.c is absent or R.sup.c is --O--, or --NR.sup.b.
2. The compound according to claim 1, have the formula (II), (III),
or (IV); ##STR00019## wherein R.sup.x1, R.sup.x2, R.sup.x3, and
R.sup.x4 are each independently H, alkyl, aryl, cyclic alkyl,
halogen, halo alkyl, heteroaryl, OR.sup.b, NR.sup.dR.sup.e,
COR.sup.b, CN, CO.sub.2R.sup.b, or CONR.sup.dR.sup.e.
3. The compound according to claim 2, wherein L.sup.1 is selected
from O and NR.sup.b.
4. The compound according to claim 3, wherein L.sup.2 is CH.sub.2,
O, or NR.sup.b.
5. The compound according to claim 4, wherein R.sup.x1, R.sup.x2,
R.sup.x3, and R.sup.x4 are each independently H, alkyl, aryl,
halogen, heteroaryl, OR.sup.b, or NR.sup.dR.sup.e.
6. The compound according to claim 5, wherein at least one
R.sup.x1, R.sup.x2, R.sup.x3, and R.sup.x4 is ##STR00020## wherein
X.sup.5 is CR.sup.x5 or N; X.sup.6 is CR.sup.x6 or N; X.sup.7 is
CR.sup.x7 or N; X.sup.8 is CR.sup.x8 or N; X.sup.9 is CR.sup.x9 or
N; X.sup.10 is CR.sup.x10 or N; Y.sub.1 is CR.sup.y1, N; O, or S;
Y.sub.2 is CR.sup.y2, N; O, or S; Y.sub.3 is CR.sup.y3, N; O, or S;
Y.sub.4 is CR.sup.y4, N; O, or S; Y.sub.5 is CR.sup.y5, N; O, or S;
R.sup.x5, R.sup.x6, R.sup.x7, R.sup.x8, R.sup.x9, and R.sup.x10 are
each independently H, alkyl, aryl, cycloalkyl, halogen, halo alkyl,
heteroaryl, OR.sup.b, NR.sup.dR.sup.e, COR.sup.b, CN,
CO.sub.2R.sup.b, or CONR.sup.dR.sup.e; R.sup.y1, R.sup.y2, R.sup.y3
and R.sup.y4 are each independently H, alkyl, aryl, cycloalkyl,
halogen, halo alkyl, heteroaryl, OR.sup.b, NR.sup.dR.sup.e,
COR.sup.b, CN, CO.sub.2R.sup.b, or CONR.sup.dR.sup.e; and R.sup.y5
is H, alkyl, aryl, alkylcarbonyl, alkoxylcarbonyl, or
heteroaryl.
7. The compound according to claim 6, wherein, one of R.sup.x2 or
R.sup.x3 is ##STR00021##
8. The compound according to claim 7, wherein L.sub.1 is --O--; and
L.sub.2 is --CH.sub.2--.
9. The compound according to claim 7, wherein L.sub.1 is
--NR.sup.b--; and L.sub.2 is --CH.sub.2--.
10. The compound according to claim 8, wherein one of R.sup.x2 or
R.sup.x3 is ##STR00022##
11. The compound according to claim 10, wherein R.sup.b is H.
12. A compound of claim 2, wherein the compound is
3H-(4's)-1'-azaspiro[benzofuran-2,4']tricyclo[3.3.1.1.sup.3,7]decane;
3H-(4's)-1'-azaspiro[5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]dec-
ane;
3H-(4's)-1'-azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,-
7]decane;
3H-(4's)-1'-azaspiro[5-(indol-5-yl)-benzofuran-2,4']-tricyclo[3.-
3.1.1.sup.3,7]decane;
3H-(4's)-1'-azaspiro[5-(indol-6-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane;
3H-(4's)-1'-azaspiro[5-(indol-4-yl)-benzofuran-2,4']-tricyclo[3.3.1.1'']d-
ecane;
3H-(4'r)-1'-azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]deca-
ne;
3H-(4'r)-1'-azaspiro[5-bromobenzofuran-2,4']tricyclo[3.3.1.1.sup.3,7]d-
ecane;
3H-(4'r)-1'-azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane;
3H-(4'r)-1'-azaspiro[5-(indol-5-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane;
3H-(4'r)-1'-azaspiro[5-(benzo[b]thiophen-5-yl)-benzofuran-2,4']-tricyclo[-
3.3.1.1.sup.3,7]decane;
3H-(4'r)-1'-azaspiro[5-(indol-4-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane;
3H-(4'r)-1'-azaspiro[5-(2-oxo-indolin-5-yl)-benzofuran-2,4']-tricyclo[3.3-
.1.1.sup.3,7]decane;
3H-(4'r)-1'-azaspiro[5-(thiophen-3-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.-
sup.3,7]decane;
3H-(4'r)-1'-azaspiro[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzofuran-2,4']-t-
ricyclo[3.3.1.1.sup.3,7]decane; or
3H-(4'r)-1'-azaspiro[5-(thieno[2,3-b]pyridin-5-yl)-benzofuran-2,4']-tricy-
clo[3.3.1.1.sup.3,7]decane.
13. A method for treating or preventing conditions, disorders, or
deficits modulated by an .alpha.7 nicotinic acetylcholine receptor,
an .alpha.4.beta.2 nicotinic acetylcholine receptor or both
.alpha.7 and .alpha.4.beta.2 nicotinic acetylcholine receptor
wherein the condition, disorder or deficit is selected from memory
disorder, cognitive disorder, neurodegeneration, and
neurodevelopmental disorder, or a combination thereof, comprising
administration of a therapeutically suitable amount of a compound
of formula (I).
14. The method according to claim 13, wherein the condition,
disorder, or deficit is selected from attention deficit disorder,
attention deficit hyperactivity disorder (ADHD), Alzheimer's
disease (AD), mild cognitive impairment, schizophrenia,
age-associated memory impairment (AAMI), senile dementia, AIDS
dementia, Pick's Disease, dementia associated with Lewy bodies,
dementia associated with Down's syndrome, amyotrophic lateral
sclerosis, Huntington's disease, smoking cessation, schizoaffective
disorder, bipolar and manic disorders, diminished CNS function
associated with traumatic brain injury, acute pain, post-surgical
pain, chronic pain, inflammatory pain, or a combination
thereof.
15. The method according to claim 13, wherein the condition,
disorder, or deficit is cognitive deficits associated with
attention deficit disorder, hyperactivity disorder, schizophrenia,
Alzheimer's disease, mild cognitive impairment, age-associated
memory impairment, or a combination thereof.
16. The method according to claim 13, further comprising
administering a compound of formula (I) in combination with an
atypical antipsychotic.
17. The method according to claim 13, wherein progression of the
condition, disorder, or deficit is improved by altering disease
modifying processes implicated in neurodegenerative diseases.
18. The method according to claim 13, wherein the condition,
disorder, or deficit is selected from infertility, lack of
circulation, need for new blood vessel growth associated with wound
healing, need for new blood vessel growth associated with
vascularization of skin grafts, ischemia, inflammation, arthritis
and related disorders, wound healing, and complications associated
with diabetes.
Description
CROSS-REFERENCE SECTION TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/876,668, filed Dec. 22, 2006, which is
hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The invention relates to spirocyclic azaadamantane
derivatives, and more particularly spirocyclic azaadamantanyl ether
or amine derivatives, compositions comprising such compounds,
methods of preventing or treating conditions and disorders using
such compounds and compositions, process for preparing such
compounds, and intermediates obtained during such processes.
[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, inflammation, psychosis, sensory
gating, mood, and emotion, among other conditions.
[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
profound physiological effects of this compound. While nicotine has
been demonstrated to have many beneficial properties, 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),
schizophrenia, Alzheimer's disease (AD), mild cognitive impairment,
senile dementia, dementia associated with Lewy bodies, dementia
associated with Down's syndrome, AIDS dementia, and Pick's Disease,
as well as inflammation. The .alpha.4.beta.2 receptor subtype is
implicated in attention, cognition, 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 some 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 new compounds that demonstrate selectivity
for .alpha.7-containing neuronal nAChRs, .alpha.4.beta.2 nAChRs, or
both .alpha.7 and .alpha.4.beta.2 nAChRs compared to other subtypes
to provide further candidates for drug development.
SUMMARY OF THE INVENTION
[0011] The invention is directed to spirocyclic azaadamantane
derivatives, compositions comprising such compounds, processes for
preparing such compounds, and intermediates obtained during such
processes. More particularly, the invention relates to spirocyclic
azaadamantanyl ether or amine compounds and related methods and
processes thereof.
[0012] One aspect of the invention relates to a compound of formula
(I)
##STR00001##
[0013] or a pharmaceutically acceptable salt or prodrug thereof,
wherein
[0014] A is N or N.sup.+--O.sup.-;
[0015] X.sup.1 is CR.sup.x1 or N;
[0016] X.sup.2 is CR.sup.x2 or N;
[0017] X.sup.3 is CR.sup.x3 or N;
[0018] X.sup.4 is CR.sup.x4 or N;
[0019] L.sup.1 and L.sup.2 are each independently --O-- and
--NR.sup.b; --R.sup.cC.dbd.O, or C.sub.1-C.sub.3 alkyl;
[0020] R.sup.x1, R.sup.x2, R.sup.x3 and R.sup.x4 are each
independently H, alkyl, aryl, cyclic alkyl, halogen, halo alkyl,
heteroaryl, OR.sup.b, NR.sup.dR.sup.e, COR.sup.b, CN,
CO.sub.2R.sup.b, or CONR.sup.dR.sup.e;
[0021] R.sup.b, R.sup.d and R.sup.e are independently H, alkyl,
aryl, alkylcarbonyl, alkoxylcarbonyl, or heteroaryl; and
[0022] R.sup.c is absent or R.sup.c is --O--, or --NR.sup.b.
[0023] 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,
.alpha.4.beta.2 nAChR activity, or both .alpha.7 nAChR activity and
.alpha.4.beta.2 nAChR activity.
[0024] Yet another aspect of the invention relates to a method of
modulating both .alpha.7 and .alpha.4.beta.2 nAChR activity. The
method is useful for treating, preventing or both treating and
preventing conditions and disorders related to both .alpha.7 and
.alpha.4.beta.2 nAChR activity, particularly in mammals.
[0025] A further aspect of the invention relates to a method of
selectively modulating nAChR activity, for example .alpha.7 nAChR
activity. The method is useful for treating, preventing or both
treating and preventing conditions and disorders related to
.alpha.7 nAChR activity 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), schizophrenia, mild cognitive impairment,
age-associated memory impairment (AAMI), senile dementia, AIDS
dementia, Pick's Disease, dementia associated with Lewy bodies,
dementia associated with Down's syndrome, schizophrenia,
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, lack of circulation, need for new blood vessel
growth associated with wound healing, more particularly circulation
around a vascular occlusion, need for new blood vessel growth
associated with vascularization of skin grafts, ischemia,
inflammation, sepsis, wound healing, and other complications
associated with diabetes, among other systemic and
neuroimmunomodulatory activities.
[0026] A method of selectively modulating nAChR activity, for
example .alpha.4.beta.2 nAChR activity, also is contemplated.
[0027] The compounds, compositions comprising the compounds,
methods for using the compounds, and processes for preparing the
compounds, as well as intermediates obtained in such processes, are
further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0028] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0029] 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.
[0030] The term "alkenylene" means a divalent group derived from a
straight or branched chain hydrocarbon of from 2 to 10 carbon atoms
containing at least one double bond. Representative examples of
alkenylene include, but are not limited to, --CH.dbd.CH--,
--CH.dbd.CH.sub.2CH.sub.2--, and
--CH.dbd.C(CH.sub.3)CH.sub.2--.
[0031] The term "alkenyloxy" as used herein, means an alkenyl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom. Representative examples of alkenyloxy
include, but are not limited to, allyloxy, 2-butenyloxy and
3-butenyloxy.
[0032] 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.
[0033] 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.
[0034] The term "alkoxyalkoxyalkyl" as used herein, means an
alkoxyalkoxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxyalkoxyalkyl include, but are not
limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl,
(2-methoxyethoxy)methyl, and 2-(2-methoxyethoxy)ethyl.
[0035] 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.
[0036] The term "alkoxycarbonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0037] The term "alkoxycarbonylalkyl" as used herein, means an
alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxycarbonylalkyl include, but are not
limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and
2-tert-butoxycarbonylethyl.
[0038] 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.
[0039] The term "alkyl" as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 10 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, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0040] 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.
[0041] The term "alkylcarbonylalkyl" as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylcarbonylalkyl include, but are not
limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and
3-oxopentyl.
[0042] 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.
[0043] The term "alkylene" means a divalent group derived from a
straight or branched chain hydrocarbon of from 1 to 10 carbon
atoms. Representative examples of alkylene include, but are not
limited to, --CH.sub.2--, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0044] The term "alkylsulfinyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfinyl group, as defined herein. Representative
examples of alkylsulfinyl include, but are not limited to,
methylsulfinyl and ethylsulfinyl.
[0045] The term "alkylsulfinylalkyl" as used herein, means an
alkylsulfinyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylsulfinylalkyl include, but are not
limited to, methylsulfinylmethyl and ethylsulfinylmethyl.
[0046] 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.
[0047] The term "alkylsulfonylalkyl" as used herein, means an
alkylsulfonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylsulfonylalkyl include, but are not
limited to, methylsulfonylmethyl and ethylsulfonylmethyl.
[0048] 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.
[0049] The term "alkylthioalkyl" as used herein, means an alkylthio
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkylthioalkyl include, but are not limited, methylthiomethyl
and 2-(ethylthio)ethyl.
[0050] 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.
[0051] The term "alkynylene" means a divalent group derived from a
straight or branched chain hydrocarbon of from 2 to 10 carbon atoms
containing at least one triple bond. Representative examples of
alkynylene include, but are not limited to, --C.ident.C--,
CH.sub.2C.ident.C--, --CH(CH.sub.3)CH.sub.2C.ident.C--,
--C.ident.CCH.sub.2--, and --C.ident.CCH(CH.sub.3)CH.sub.2--.
[0052] The term "alkynyloxy" as used herein, means an alkynyl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom. Representative examples of alkynyloxy
include, but are not limited to, 2-propynyloxy and
2-butynyloxy.
[0053] The term "aryl," as used herein, means phenyl, a bicyclic
aryl or a tricyclic aryl. The bicyclic aryl is naphthyl, a phenyl
fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl.
Representative examples of the bicyclic aryl include, but are not
limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl,
and tetrahydronaphthalenyl. The tricyclic aryl is anthracene or
phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a
bicyclic aryl fused to a cycloalkenyl, or a bicyclic aryl fused to
a phenyl. Representative examples of tricyclic aryl ring include,
but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl,
and tetrahydrophenanthrenyl.
[0054] The aryl groups of this invention can be substituted with 1,
2, 3, 4 or 5 substituents independently selected from alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl,
alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio,
alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,
formyl, formylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl,
mercapto, nitro, --NZ.sub.1Z.sub.2, and
(NZ.sub.3Z.sub.4)carbonyl.
[0055] The term "arylalkoxy" as used herein, means an aryl group,
as defined herein, appended to the parent molecular moiety through
an alkoxy group, as defined herein. Representative examples of
arylalkoxy include, but are not limited to, 2-phenylethoxy,
3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
[0056] The term "arylalkoxycarbonyl" as used herein, means an
arylalkoxy group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of arylalkoxycarbonyl include, but are not
limited to, benzyloxycarbonyl and naphth-2-ylmethoxycarbonyl.
[0057] The term "arylalkyl" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl, 2-phenylethyl,
3-phenylpropyl, and 2-naphth-2-ylethyl.
[0058] The term "arylalkylthio" as used herein, means an arylalkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfur atom. Representative examples of arylalkylthio
include, but are not limited to, 2-phenylethylthio,
3-naphth-2-ylpropylthio, and 5-phenylpentylthio.
[0059] The term "arylcarbonyl" as used herein, means an aryl group,
as defined herein, appended to the parent molecular moiety through
a carbonyl group, as defined herein. Representative examples of
arylcarbonyl include, but are not limited to, benzoyl and
naphthoyl.
[0060] The term "aryloxy" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of aryloxy include, but are
not limited to, phenoxy, naphthyloxy, 3-bromophenoxy,
4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.
[0061] The term "aryloxyalkyl" as used herein, means an aryloxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl,
3-naphth-2-yloxypropyl and 3-bromophenoxymethyl.
[0062] The term "arylthio" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through a
sulfur atom. Representative examples of arylthio include, but are
not limited to, phenylthio and 2-naphthylthio.
[0063] The term "arylthioalkyl" as used herein, means an arylthio
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of arylthioalkyl include, but are not limited to, phenylthiomethyl,
2-naphth-2-ylthioethyl, and 5-phenylthiomethyl.
[0064] The term "azido" as used herein, means a --N.sub.3
group.
[0065] The term "carbonyl" as used herein, means a --C(O)--
group.
[0066] The term "carboxy" as used herein, means a --CO.sub.2H
group.
[0067] The term "carboxyalkyl" as used herein, means a carboxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of carboxyalkyl include, but are not limited to, carboxymethyl,
2-carboxyethyl, and 3-carboxypropyl.
[0068] The term "cyano" as used herein, means a --CN group.
[0069] The term "cyanoalkyl" as used herein, means a cyano group,
as defined herein, appended to the parent molecular moiety through
an alkyl group, as defined herein. Representative examples of
cyanoalkyl include, but are not limited to, cyanomethyl,
2-cyanoethyl, and 3-cyanopropyl.
[0070] The term "cycloalkenyl" as used herein, means a cyclic
hydrocarbon containing from 3 to 8 carbons and containing at least
one carbon-carbon double bond formed by the removal of two
hydrogens. Representative examples of cycloalkenyl include, but are
not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,
2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.
[0071] The term "cycloalkyl" as used herein, means a monocyclic,
bicyclic, or tricyclic ring system. Monocyclic ring systems are
exemplified by a saturated cyclic hydrocarbon group containing from
3 to 8 carbon atoms. Examples of monocyclic ring systems include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. Bicyclic ring systems are exemplified by a bridged
monocyclic ring system in which two adjacent or non-adjacent carbon
atoms of the monocyclic ring are linked by an alkylene bridge of
between one and three additional carbon atoms. Tricyclic ring
systems are exemplified by a bicyclic ring system in which two
non-adjacent carbon atoms of the bicyclic ring are linked by a bond
or an alkylene bridge of between one and three carbon atoms.
Representative examples of tricyclic-ring systems include, but are
not limited to, tricyclo[3.3.1.0.sup.3,7]nonane and
tricyclo[3.3.1.1.sup.3,7]decane (adamantane).
[0072] The cycloalkyl groups of the invention are optionally
substituted with 1, 2, 3, 4 or 5 substituents selected from the
group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl,
alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, mercapto, oxo, --NZ.sub.1Z.sub.2, and
(NZ.sub.3Z.sub.4)carbonyl.
[0073] The term "cycloalkylalkyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
[0074] The term "cycloalkylcarbonyl" as used herein, means
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of cycloalkylcarbonyl include, but are not
limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and
cyclohexylcarbonyl.
[0075] The term "cycloalkyloxy" as used herein, means cycloalkyl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom, as defined herein. Representative examples
of cycloalkyloxy include, but are not limited to, cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and
cyclooctyloxy.
[0076] The term "cycloalkylthio" as used herein, means cycloalkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfur atom, as defined herein. Representative examples
of cycloalkylthio include, but are not limited to, cyclopropylthio,
cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio,
and cyclooctylthio.
[0077] The term "ethylenedioxy" as used herein, means a
--O(CH.sub.2).sub.2O-- group wherein the oxygen atoms of the
ethylenedioxy group are attached to the parent molecular moiety
through one carbon atom forming a 5 membered ring or the oxygen
atoms of the ethylenedioxy group are attached to the parent
molecular moiety through two adjacent carbon atoms forming a six
membered ring.
[0078] The term "formyl" as used herein, means a --C(O)H group.
[0079] The term "formylalkyl" as used herein, means a formyl group,
as defined herein, appended to the parent molecular moiety through
an alkyl group, as defined herein. Representative examples of
formylalkyl include, but are not limited to, formylmethyl and
2-formylethyl.
[0080] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0081] 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.
[0082] 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.
[0083] The term "heteroaryl." as used herein, means a monocyclic
heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a
5 or 6 membered ring that contains at least one heteroatom selected
from the group consisting of nitrogen, oxygen and sulfur. The 5
membered ring contains two double bonds and the 6 membered ring
contains three double bonds. The 5 or 6 membered heteroaryl is
connected to the parent molecular moiety through any carbon atom or
any substitutable nitrogen atom contained within the heteroaryl,
provided that proper valance is maintained. Representative examples
of monocyclic heteroaryl include, but are not limited to, furyl,
imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,
pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,
and triazinyl. The bicyclic heteroaryl consists of a monocyclic
heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a
cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or
a monocyclic heteroaryl fused to a monocyclic heteroaryl. The
bicyclic heteroaryl is connected to the parent molecular moiety
through any carbon atom or any substitutable nitrogen atom
contained within the bicyclic heteroaryl, provided that proper
valance is maintained. Representative examples of bicyclic
heteroaryl include, but are not limited to, azaindolyl,
benzimidazolyl, benzofuranyl, benzoxadiazolyl, benzoisoxazole,
benzoisothiazole, benzooxazole, 1,3-benzothiazolyl,
benzothiophenyl, cinnolinyl, furopyridine, indolyl, indazolyl,
isobenzofuran, isoindolyl, isoquinolinyl, naphthyridinyl,
oxazolopyridine, quinolinyl, quinoxalinyl and thienopyridinyl.
[0084] The heteroaryl groups of the invention are optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl,
alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy,
alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano,
cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl, mercapto, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl. Heteroaryl groups of the invention that
are substituted with a hydroxyl group may be present as tautomers.
The heteroaryl groups of the invention encompasses all tautomers
including non-aromatic tautomers.
[0085] The term "heteroarylalkoxy" as used herein, means a
heteroaryl group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of heteroarylalkoxy include, but are not
limited to, fur-3-ylmethoxy, 1H-imidazol-2-ylmethoxy,
1H-imidazol-4-ylmethoxy, 1-(pyridin-4-yl)ethoxy,
pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy,
pyridin-4-ylmethoxy, (6-(trifluoromethyl)pyridin-3-yl)methoxy,
(6-(cyano)pyridin-3-yl)methoxy, (2-(cyano)pyridin-4-yl)methoxy,
(5-(cyano)pyridin-2-yl)methoxy, (2-(chloro)pyridin-4-yl)methoxy,
pyrimidin-5-ylmethoxy, 2-(pyrimidin-2-yl)propoxy,
thien-2-ylmethoxy, and thien-3-ylmethoxy.
[0086] The term "heteroarylalkyl" as used herein, means a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of heteroarylalkyl include, but are not limited to,
fur-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,
1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl,
6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl,
(6-(trifluoromethyl)pyridin-3-yl)methyl,
(6-(cyano)pyridin-3-yl)methyl, (2-(cyano)pyridin-4-yl)methyl,
(5-(cyano)pyridin-2-yl)methyl, (2-(chloro)pyridin-4-yl)methyl,
pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl,
and thien-3-ylmethyl.
[0087] The term "heteroarylalkylcarbonyl" as used herein, means a
heteroarylalkyl, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0088] The term "heteroarylalkylthio" as used herein, means a
heteroarylalkyl group, as defined herein, appended to the parent
molecular moiety through a sulfur atom. Representative examples of
heteroarylalkylthio include, but are not limited to,
fur-3-ylmethylthio, 1H-imidazol-2-ylmethylthio,
1H-imidazol-4-ylmethylthio, pyridin-3-ylmethylthio,
6-chloropyridin-3-ylmethylthio, pyridin-4-ylmethylthio,
(6-(trifluoromethyl)pyridin-3-yl)methylthio,
(6-(cyano)pyridin-3-yl)methylthio,
(2-(cyano)pyridin-4-yl)methylthio,
(5-(cyano)pyridin-2-yl)methylthio,
(2-(chloro)pyridin-4-yl)methylthio, pyrimidin-5-ylmethylthio,
2-(pyrimidin-2-yl)propylthio, thien-2-ylmethylthio, and
thien-3-ylmethylthio.
[0089] The term "heteroarylcarbonyl" as used herein, means a
heteroaryl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of heteroarylcarbonyl include, but are not
limited to, fur-3-ylcarbonyl, 1H-imidazol-2-ylcarbonyl,
1H-imidazol-4-ylcarbonyl, pyridin-3-ylcarbonyl,
6-chloropyridin-3-ylcarbonyl, pyridin-4-ylcarbonyl,
(6-(trifluoromethyl)pyridin-3-yl)carbonyl,
(6-(cyano)pyridin-3-yl)carbonyl, (2-(cyano)pyridin-4-yl)carbonyl,
(5-(cyano)pyridin-2-yl)carbonyl, (2-(chloro)pyridin-4-yl)carbonyl,
pyrimidin-5-ylcarbonyl, pyrimidin-2-ylcarbonyl, thien-2-ylcarbonyl,
and thien-3-ylcarbonyl.
[0090] The term "heteroaryloxy" as used herein, means a heteroaryl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom. Representative examples of heteroaryloxy
include, but are not limited to, fur-3-yloxy, 1H-imidazol-2-yloxy,
1H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy,
pyridin-4-yloxy, (6-(trifluoromethyl)pyridin-3-yl)oxy,
(6-(cyano)pyridin-3-yl)oxy, (2-(cyano)pyridin-4-yl)oxy,
(5-(cyano)pyridin-2-yl)oxy, (2-(chloro)pyridin-4-yl)oxy,
pyrimidin-5-yloxy, pyrimidin-2-yloxy, thien-2-yloxy, and
thien-3-yloxy.
[0091] The term "heteroaryloxyalkyl" as used herein, means a
heteroaryloxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heteroaryloxyalkyl include, but are not
limited to, pyridin-3-yloxymethyl and 2-quinolin-3-yloxyethyl.
[0092] The term "heteroarylthio" as used herein, means a heteroaryl
group, as defined herein, appended to the parent molecular moiety
through a sulfur atom. Representative examples of heteroarylthio
include, but are not limited to, pyridin-3-ylthio and
quinolin-3-ylthio.
[0093] The term "heteroarylthioalkyl" as used herein, means a
heteroarylthio group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heteroarylthioalkyl include, but are not
limited to, pyridin-3-ylthiomethyl, and
2-quinolin-3-ylthioethyl.
[0094] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic heterocycle, a bicyclic heterocycle or a
tricyclic 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 O, N, and S. The 3 or 4
membered ring contains 1 heteroatom selected from the group
consisting of O, N and S. The 5 membered ring contains zero or one
double bond and one, two or three heteroatoms selected from the
group consisting of O, N and S. 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 O, N and S. 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, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,
pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl,
and trithianyl. The bicyclic heterocycle is a 5 or 6 membered
monocyclic heterocycle fused to a phenyl group, or a 5 or 6
membered monocyclic heterocycle fused to a cycloalkyl, or a 5 or 6
membered monocyclic heterocycle fused to a cycloalkenyl, or a 5 or
6 membered monocyclic heterocycle fused to a monocyclic
heterocycle. The bicyclic heterocycle is connected to the parent
molecular moiety through any carbon atom or any nitrogen atom
contained within the bicyclic heterocycle. Representative examples
of bicyclic heterocycle include, but are not limited to,
1,3-benzodioxolyl, 1,3-benzodithiolyl,
2,3-dihydro-1,4-benzodioxinyl, benzodioxolyl,
2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, chromenyl
and 1,2,3,4-tetrahydroquinolinyl. The tricyclic heterocycle is a
bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle
fused to a cycloalkyl, or a bicyclic heterocycle fused to a
cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic
heterocycle. The tricyclic heterocycle is connected to the parent
molecular moiety through any carbon atom or any nitrogen atom
contained within the tricyclic heterocycle. Representative examples
of tricyclic heterocycle include, but are not limited to,
2,3,4,4a,9,9a-hexahydro-1H-carbazolyl,
5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and
5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.
[0095] The heterocycles of this invention are optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl,
alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy,
alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano,
cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl, mercapto, oxo, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl.
[0096] The term "heterocyclealkoxy" as used herein, means a
heterocycle group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of heterocyclealkoxy include, but are not
limited to, 2-pyridin-3-ylethoxy, 3-quinolin-3-ylpropoxy, and
5-pyridin-4-ylpentyloxy.
[0097] The term "heterocyclealkyl" as used herein, means a
heterocycle, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of heterocyclealkyl include, but are not limited to,
[0098] The term "heterocyclealkylcarbonyl" as used herein, means a
heterocyclealkyl, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of heterocyclealkylcarbonyl include, but
are not limited to, piperidin-4-ylmethylcarbonyl,
piperazin-1-ylmethylcarbonyl,
3-methyl-1-pyrrolidin-1-ylbutylcarbonyl,
(1R)-3-methyl-1-pyrrolidin-1-ylbutylcarbonyl,
(1S)-3-methyl-1-pyrrolidin-1-ylbutylcarbonyl.
[0099] The term "heterocycleallylthio" as used herein, means a
heterocyclealkyl group, as defined herein, appended to the parent
molecular moiety through a sulfur atom. Representative examples of
heterocyclealkylthio include, but are not limited to,
2-pyridin-3-ylethylhio, 3-quinolin-3-ylpropythio, and
5-pyridin-4-ylpentylthio.
[0100] The term "heterocyclecarbonyl" as used herein, means a
heterocycle, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.
[0101] The term "heterocyclecarbonylalkyl" as used herein, means a
heterocyclecarbonyl, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0102] The term "heterocycleoxy" as used herein, means a
heterocycle group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
heterocycleoxy include, but are not limited to, pyridin-3-yloxy and
quinolin-3-yloxy.
[0103] The term "heterocycleoxyalkyl" as used herein, means a
heterocycleoxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heterocycleoxyalkyl include, but are not
limited to, pyridin-3-yloxymethyl and 2-quinolin-3-yloxyethyl.
[0104] The term "heterocyclethio" as used herein, means a
heterocycle group, as defined herein, appended to the parent
molecular moiety through a sulfur atom. Representative examples of
heterocyclethio include, but are not limited to, pyridin-3-ylthio
and quinolin-3-ylthio.
[0105] The term "heterocyclethioalkyl" as used herein, means a
heterocyclethio group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heterocyclethioalkyl include, but are
not limited to, pyridin-3-ylthiomethyl, and
2-quinolin-3-ylthioethyl.
[0106] The term "hydroxyl" as used herein, means an --OH group.
[0107] 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.
[0108] The term "hydroxy-protecting group" or "O-protecting group"
means a substituent which protects hydroxyl groups against
undesirable reactions during synthetic procedures. Examples of
hydroxy-protecting groups include, but are not limited to,
substituted methyl ethers, for example, methoxymethyl,
benzyloxymethyl, 2-methoxyethoxymethyl,
2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl;
tetrahydropyranyl ethers; substituted ethyl ethers, for example,
2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,
trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl;
cyclic acetals and ketals, for example, methylene acetal, acetonide
and benzylidene acetal; cyclic ortho esters, for example,
methoxymethylene; cyclic carbonates; and cyclic boronates. Commonly
used hydroxy-protecting groups are disclosed in T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition,
John Wiley & Sons, New York (1999).
[0109] The term "lower alkenyl" as used herein, is a subset of
alkenyl, as defined herein, and means an alkenyl group containing
from 2 to 4 carbon atoms. Examples of lower alkenyl are ethenyl,
propenyl, and butenyl.
[0110] The term "lower alkoxy" as used herein, is a subset of
alkoxy, as defined herein, and means a lower alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom, as defined herein. Representative examples of lower
alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, and tert-butoxy.
[0111] The term "lower alkyl" as used herein, is a subset of alkyl
as defined herein and means a straight or branched chain
hydrocarbon group containing from 1 to 4 carbon atoms. Examples of
lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, and tert-butyl.
[0112] The term "lower alkylthio" as used herein, is a subset of
alkylthio, means a lower alkyl group, as defined herein, appended
to the parent molecular moiety through a sulfur atom.
Representative examples of lower alkylthio include, but are not
limited, methylthio, ethylthio, and tert-butylthio.
[0113] The term "lower alkynyl" as used herein, is a subset of
alkynyl, as defined herein, and means an alkynyl group containing
from 2 to 4 carbon atoms. Examples of lower alkynyl are ethynyl,
propynyl, and butynyl.
[0114] The term "lower haloalkoxy" as used herein, is a subset of
haloalkoxy, as defined herein, and means a straight or branched
chain haloalkoxy group containing from 1 to 4 carbon atoms.
Representative examples of lower haloalkoxy include, but are not
limited to, trifluoromethoxy, trichloromethoxy, dichloromethoxy,
fluoromethoxy, and pentafluoroethoxy.
[0115] The term "lower haloalkyl" as used herein, is a subset of
haloalkyl, as defined herein, and means a straight or branched
chain haloalkyl group containing from 1 to 4 carbon atoms.
Representative examples of lower haloalkyl include, but are not
limited to, trifluoromethyl, trichloromethyl, dichloromethyl,
fluoromethyl, and pentafluoroethyl.
[0116] The term "mercapto" as used herein, means a --SH group.
[0117] The term "mercaptoalkyl" as used herein, means a mercapto
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of mercaptoalkyl include, but are not limited to, 2-mercaptoethyl
and 3-mercaptopropyl.
[0118] The term "methylenedioxy" as used herein, means a
--OCH.sub.2O-- group wherein the oxygen atoms of the methylenedioxy
are attached to the parent molecular moiety through two adjacent
carbon atoms.
[0119] The term "nitrogen protecting group" as used herein, means
those groups intended to protect an amino group against undesirable
reactions during synthetic procedures. Preferred nitrogen
protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl
(Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc),
tert-butylacetyl, trifluoroacetyl, and triphenylmethyl
(trityl).
[0120] The term "nitro" as used herein, means a --NO, group.
[0121] The term "NZ.sub.1Z.sub.2" as used herein, means two groups,
Z.sub.1 and Z.sub.2, which are appended to the parent molecular
moiety through a nitrogen atom, Z.sub.1 and Z.sub.2 are each
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, formyl and
(NZ.sub.5Z.sub.6)carbonyl. In certain instances within the
invention. Z.sub.1 and Z.sub.2 taken together with the nitrogen
atom to which they are attached form a heterocyclic ring.
Representative examples of NZ.sub.1Z.sub.2 include, but are not
limited to, amino, methylamino, acetylamino, acetylmethylamino,
phenylamino, benzylamino, azetidinyl, pyrrolidinyl and
piperidinyl.
[0122] The term "NZ.sub.3Z.sub.4" as used herein, means two groups,
Z.sub.3 and Z.sub.4, which are appended to the parent molecular
moiety through a nitrogen atom. Z.sub.3 and Z.sub.4 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and arylalkyl. Representative examples of
NZ.sub.3Z.sub.4 include, but are not limited to, amino,
methylamino, phenylamino and benzylamino.
[0123] The term "NZ.sub.5Z.sub.6" as used herein, means two groups,
Z.sub.5 and Z.sub.6, which are appended to the parent molecular
moiety through a nitrogen atom. Z.sub.5 and Z.sub.6 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and arylalkyl. Representative examples of
NZ.sub.5Z.sub.6 include, but are not limited to, amino,
methylamino, phenylamino and benzylamino.
[0124] The term "(NZ.sub.3Z.sub.4)carbonyl" as used herein, means a
NZ.sub.3Z.sub.4 group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples or (NZ.sub.3Z.sub.4)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0125] The term "oxo" as used herein, means a .dbd.O moiety.
[0126] The term "sulfinyl" as used herein, means a --S(O)--
group.
[0127] The term "sulfonyl" as used herein, means a --SO.sub.2--
group.
[0128] The term "tautomer" as used herein means a proton shift from
one atom of a compound to another atom of the same compound wherein
two or more structurally distinct compounds are in equilibrium with
each other.
[0129] 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.3b4* 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
[0130] Compounds of the invention can have the formula (I) as
described in the Summary of the Invention.
[0131] Within the scope of the invention, the compounds of the
invention have the formula (II), (III), (IV)
##STR00002##
[0132] wherein L.sup.1, L.sup.2, R.sup.x1, R.sup.x2, R.sup.x3, and
R.sup.x4 are each independently defined in formula (I).
[0133] In one embodiment, the compounds of the invention can have
the formula (II), (III) or (IV), wherein L.sup.2, R.sup.x1,
R.sup.x2, R.sup.x3, and R.sup.x4 are as described in formula (I):
L.sup.1 is selected from O and NR.sup.b.
[0134] In another embodiment, compounds of the invention can have
the formula (II), (III) or (IV), wherein R.sup.x1, R.sup.x2,
R.sup.x3, and R.sup.x4 are as described in formula (I). L.sup.1 is
selected from O and NR.sup.b. L.sup.2 is selected from CH.sub.2, O,
and NR.sup.b.
[0135] In one more embodiment, compounds of the invention can have
the formula (II), (III) or (IV), wherein L.sup.1 is selected from O
and NR.sup.b. L.sup.2 is selected from CH.sub.2, O, NR.sup.b,
R.sup.x1, R.sup.x2, R.sup.x3, and R.sup.x4 are particularly
selected from H, alkyl, aryl, halogen, heteroaryl, OR.sup.b, and
NR.sup.dR.sup.e, and more particularly selected from aryl and
heteroaryl groups having the structures
##STR00003##
[0136] wherein
[0137] X.sup.5 is CR.sup.x5 or N;
[0138] X.sup.6 is CR.sup.x6 or N;
[0139] X.sup.7 is CR.sup.x7 or N;
[0140] X.sup.8 is CR.sup.x8 or N;
[0141] X.sup.9 is CR.sup.x9 or N;
[0142] X.sup.10 is CR.sup.x10 or N;
[0143] Y.sub.1 is CR.sup.y1, N; O, or S;
[0144] Y.sub.2 is CR.sup.y2, N; O, or S;
[0145] Y.sub.3 is CR.sup.y3, N; O, or S;
[0146] Y.sup.4 is CR.sup.y4, N; O, or S;
[0147] Y.sub.5 is CR.sup.y5, N; O, or S:
[0148] R.sup.x5, R.sup.x6, R.sup.x7, R.sup.x8, R.sup.x9, and
R.sup.x10 are each independently H, alkyl, aryl, cycloalkyl,
halogen, halo alkyl, heteroaryl, OR.sup.b, NR.sup.dR.sup.e,
COR.sup.b, CN, CO.sub.2R.sup.b, or CONR.sup.dR.sup.e;
[0149] R.sup.y1, R.sup.y2, R.sup.y3 and R.sup.y4 are each
independently H, alkyl, aryl, cycloalkyl, halogen, halo alkyl,
heteroaryl, OR.sup.b, NR.sup.dR.sup.c, COR.sup.b, CN,
CO.sub.2R.sup.b, or CONR.sup.dR.sup.e, and
[0150] R.sup.y5 is H, alkyl, aryl, alkylcarbonyl, alkoxylcarhonyl,
or heteroaryl.
[0151] Examples or specific aryl and heteroaryl groups suitable for
compounds of formula (V), (VI), and (VII) include, but are not
limited to imidazolyl, isoimidazolyl, isoxazolyl, isothiazolyl,
furyl, oxazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl,
pyrazinyl, thiophenyl, 1,3-thiazolyl, 1,3,4-oxadiazolyl,
benzofuranyl, benzo[d]imidazolyl, benzo[d]isoxazolyl,
benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl,
benzo[b]thiophenyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl,
imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridine, indolyl,
indazolyl, isoxazolo[4,5-b]pyridinyl, isoxazolo[4,5-c]pyridinyl,
isoxazolo[5,4-b]pyridinyl, isoxazolo[5,4-c]pyridinyl,
isothiazolo[4,5-c]pyridinyl, isothiazolo[4,5-c]pyridinyl,
isothiazolo[5,4-b]pyridinyl, isothiazolo[5,4-c]pyridinyl,
oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl,
oxazolo[5,4-b]pyridinyl, oxazolo[5,4-c]pyridinyl,
pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl,
pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-c]pyridinyl,
pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,
pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl,
thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl,
thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl. Preferred aryl
and heteroaryl groups are indolyl, phenyl, pyridinyl, pyrazolyl,
and pyrrolopyridinyl. The individual corresponding aryl and
heteroaryl groups can be optionally substituted with 0, 1, 2, 3, 4
or 5 substituents selected from H, alkyl, aryl, cyclic alkyl,
halogen, halo alkyl, heteroaryl, OR.sup.b, NR.sup.dR.sup.c,
COR.sup.b, CN, CO.sub.2R.sup.b, and CONR.sup.dR.sup.e.
[0152] Specific embodiments contemplated as part of the invention
include, but are not limited to compounds of formula (I), salts, or
prodrugs thereof, for example: [0153]
3H-(4's)-1'-azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane;
[0154]
3H-(4's)-1'-azaspiro[5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane; [0155]
3H-(4's)-1'-azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]de-
cane; [0156]
3H-(4's)-1'-azaspiro[5-(indol-5-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane; [0157]
3H-(4's)-1'-azaspiro[5-(indol-6-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane; [0158]
3H-(4's)-1'-azaspiro[5-(indol-4-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane; [0159]
3H-(4'r)-1'-azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane;
[0160]
3H-(4'r)-1'-azaspiro[5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane; [0161]
3H-4'r)-1'-azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]dec-
ane; [0162]
3H-(4'r)-1'-azaspiro[5-(indol-5-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane; [0163]
3H-(4'r)-1'-azaspiro[5-(benzo[b]thiophen-5-yl)-benzofuran-2,4']-tricyclo[-
3.3.1.1.sup.3,7]decane; [0164]
3H-(4'r)-1'-azaspiro[5-(indol-4-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup-
.3,7]decane; [0165]
3H-(4'r)-1'-azaspiro[5-(2-oxo-indolin-5-yl)-benzofuran-2,4]-tricyclo[3.3.-
1.1.sup.3,7]decane; [0166]
3H-(4'r)-1'-azaspiro[5-(thiophen-3-yl)-benzofuran-2,4]-tricyclo[3.3.1.1.s-
up.3,7]decane; [0167]
3H-(4'r)-1'-azaspiro[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzofuran-2,4']-t-
ricyclo[3.3.1.1.sup.3,7]decane; and [0168]
3H-(4'r)-1'-azaspiro[5-(thieno[2,3-b]pyridin-5-yl)-benzofuran-2.4]-tricyc-
lo[3.3.1.1.sup.3,7]decane.
[0169] 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. 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.
[0170] More particularly, the compounds of the invention can exist
in the forms represented by formulas
##STR00004##
[0171] The aza-adamantane portion of isomer (Ia) and isomer (Ib) is
not chiral, however the C-4 carbon at which L.sub.1 is attached is
considered pseudoasymmetric. Compounds represented by formula (Ia)
and (Ib) are diastereomers. The configurational assignment of
structures of formula (Ia) are assigned 4s 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 (Ib) are
assigned 4r using the same methods.
[0172] The isomers (Ia) and (Ib) may be synthesized separately
using the individual stereoisomers according to the Schemes or the
Experimentals described herein. Alternatively, isomers (Ia) and
(Ib) may be synthesized together after which the individual isomers
may be separated by chromatographic methods from the mixture of
both isomers when mixtures of stereoisomers are used in the
synthesis.
[0173] It is contemplated that a mixture of both isomers may be
used to modulate the effects of nAChRs. Furthermore, it is
contemplated that the individual isomers of formula (Ia) and (Ib)
may be used alone to modulate the effects of nAChRs. Therefore, it
is contemplated that either a mixture of the compounds of formula
(Ia) and (Ib) or the individual isomers alone represented by the
compounds of formula (Ia) or (Ib) would be effective in modulating
the effects of nAChRs, and more particularly .alpha.7 nAChRs and is
thus within the scope of the invention.
Methods of the Invention
[0174] 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 or 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.
[0175] In addition, the invention relates to a method for treating
or preventing conditions, disorders or deficits modulated by an
.alpha.7 nicotinic acetylcholine receptor, an .alpha.4.beta.2
nicotinic acetylcholine receptor or both .alpha.7 and
.alpha.4.beta.2 nicotinic acetylcholine receptors wherein the
condition, disorder, or deficit is selected from the group
consisting of a memory disorder, cognitive disorder,
neurodegeneration, or neurodevelopmental disorder, or a combination
thereof, comprising administration of a therapeutically suitable
amount of a compound of formula (I).
##STR00005##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
A, L.sup.1, L.sup.2, X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are as
previously defined.
[0176] The invention also contemplates the method for treating or
preventing a condition or disorder modulated by an .alpha.7
nicotinic acetylcholine receptor comprising the step of
administering a compound of the formula (I), wherein the condition
or disorder is selected from a memory disorder, cognitive disorder,
neurodegeneration, and neurodevelopmental disorder.
[0177] The invention also contemplates a method for treating or
preventing a condition or disorder modulated by an .alpha.7
nicotinic acetylcholine receptor comprising the step of
administering a compound of the formula (I), wherein the condition
or disorder is selected from attention deficit disorder, attention
deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD),
mild cognitive impairment, schizophrenia, 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, and inflammatory pain.
[0178] The invention also contemplates a method for treating or
preventing a condition or disorder modulated by an .alpha.7
nicotinic acetylcholine receptor comprising the step of
administering a compound of the formula (I), wherein the condition
or disorder is schizophrenia.
[0179] The invention also contemplates a method for treating or
preventing a condition or disorder modulated by an .alpha.7
nicotinic acetylcholine receptor comprising the step of
administering a compound of the formula (I) in combination with an
atypical antipsychotic.
[0180] The invention also contemplates a method for treating or
preventing a condition or disorder modulated by an .alpha.7
nicotinic acetylcholine receptor comprising the step of
administering a compound of the formula (I), wherein the condition
or disorder is infertility, lack of circulation, need for new blood
vessel growth associated with wound healing, more particularly
circulation around a vascular occlusion, need for new blood vessel
growth associated with vascularization of skin grafts, ischemia,
inflammation, particularly those associated with rheumatoid
arthritis, wound healing, and other complications associated with
diabetes.
[0181] The invention also contemplates a method for treating or
preventing a condition or disorder modulated both by .alpha.7 and
.alpha.4.beta.2 nicotinic acetylcholine receptor comprising the
step of administering a compound of the formula (I), wherein the
condition or disorder is selected from a group of disorders where
both .alpha.7 and .alpha.4.beta.2 nicotinic receptors are
implicated. These include attention deficit disorder, attention
deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD),
mild cognitive impairment, schizophrenia, senile dementia, AIDS
dementia, Pick's Disease, dementia associated with Lewy bodies,
dementia associated with Down's syndrome, amyotrophic lateral
sclerosis, Huntington's disease, inflammation, arthritis of various
types, smoking cessation, traumatic brain injury, acute pain,
post-surgical pain, osteoarthritic pain, neuropathic, and
inflammatory chronic pain states.
[0182] 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. Certain compounds of the invention
demonstrate, in addition to affinity for .alpha.7 nAChRs, affinity
for .alpha.4.beta.2 nAChRs.
[0183] 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 conditions and disorders related to memory, cognition,
or both 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.
[0184] In addition, .alpha.7-containing nAChRs have been shown to
be involved in the cytoprotective 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
.beta.-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). .alpha.7 selective ligands can influence
neuroprotective pathways leading to decreased phosphorylation of
the tau protein, whose hyperphosphorylation is required for
neurofibrillary tangle formation in various tau related pathologies
such as Alzheimer's disease and various other dementias (Bitner et
al., Soc Neuroscience, 2006 abst 325.6). 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.
[0185] Alpha-7 nAChRs also have been implicated in aspects of
neurodevelopment, for example neurogenesis of the brain. (Falk, L.
et al. Developmental Brain Research 142:151-160, 2003; Tsuneki, H.,
et al. J. Physiol. (London) 547:169-179, 2003; Adams, C. E., et
al., Developmental Brain Research 139:175-187, 2002). As such,
.alpha.7 nAChRs can be useful in preventing or treating conditions
or disorders associated with impaired neurodevelopment, for example
schizophrenia. (Sawa A., Mol. Med. 9:3-9, 2003).
[0186] Several compounds with high affinity for .alpha.4.beta.2
NNRs have been shown to improve attentive and cognitive performance
in preclinical models that are relevant to
attention-deficit/hyperactivity disorder (ADHD), a disease
characterized by core symptoms of hyperactivity, inattentiveness,
and impulsivity. For example, ABT-418, a full agonist at
.alpha.4.beta.2 NNRs, is efficacious in a variety of preclinical
cognition models. ABT-418 administered transdermally, was shown in
a controlled clinical trial in 32 adults to be effective in
treating ADHD in general, and attentional/cognitive deficits in
particular (Wilens et al 1999). Likewise, ABT-418 showed a signal
of efficacy in a pilot Alzheimer's disease trial. ABT-089, a
.alpha.4.beta.2 selective partial agonist, has been shown in rodent
and primate animal models to improve attention, learning, and
memory deficits. ABT-089 and another .alpha.4.beta.2 agonist,
ispronicline, has shown efficacy in a pilot clinical trials. In
addition to cognition, compounds that interact with .alpha.4.beta.2
nAChRs such as ABT-594 and others are also efficacious in
preclinical and clinical models of pain. As such, ligands that
modulate both .alpha.7 and .alpha.4.beta.2 activity can have
broader spectrum of therapeutic efficacy in disease states such as
those involving cognitive deficits, attentive deficits, pain,
neurodegenerative diseases, and others.
[0187] 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
post-mortem patients (Sawa A. Mol. Med. 9:3-9, 2003: 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). More recent studies have shown that .alpha.4.beta.2
nicotinic receptor stimulation also contributes to the effects of
nicotine in the DBA/2 mouse model of sensory gating (Radek et al.,
Psychopharmacology (Berl), 2006 187:47-55. Thus, .alpha.7 and
.alpha.7/.alpha.4.beta.2 ligands demonstrate potential in the
treatment schizophrenia.
[0188] 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). For example, improved conditions
related to inflammation, ischemia, cardiac ischemia, and wound
healing, for example in diabetic persons, have been associated with
.alpha.7 nAChR activity (Jacobi, J., et al. Am. J. Pathol.
161:97-104, 2002). Therefore, nAChR ligands that are selective for
the .alpha.7 subtype offer improved potential for stimulating
angiogenesis with an improved side effect profile.
[0189] A population of .alpha.7 or .alpha.4.beta.2 nAChRs in the
spinal cord modulate neurotransmission 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 and .alpha.7/.alpha.4.beta.2 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
inflammation including those associated with various forms of
arthritis.
[0190] 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.
[0191] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting memory,
cognition, neurodegeneration, neurodevelopment, and
schizophrenia.
[0192] 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,
(Friedman, J. I. et al. Biol Psychiatry. 51: 349-357, 2002). 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.
[0193] 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
considering the composition and the method 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.
[0194] 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.
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. 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.
[0195] The total daily dose of the compounds of this invention
administered to a human or lower animal range from about 0.10
.mu.g/kg body weight to about 10 mg/kg body weight. More preferable
doses can be in the range of from about 0.10 .mu.g/kg body weight
to about 1 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.
Methods for Preparing Compounds of the Invention
[0196] As used in the descriptions of the schemes and the examples,
certain abbreviations are intended to have the following meanings:
Bu for butyl; DMAP for 4-dimethylaminopyridine; DMF for dimethyl
formamide: DME for 1,2-dimethoxyethane; Et for ethyl; EtOAc for
ethyl acetate; HPLC for high pressure liquid chromatography; Me for
methyl; MeOH for methanol: OAc for acetoxy; Pd/C for palladium on
carbon: Ph for phenyl; and THF for tetrahydrofuran.
[0197] 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.
[0198] 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 trifluoroacetyl.
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 trifluoroacetyl protecting groups may
be removed by a hydroxide ion.
##STR00006##
[0199] As outlined in Scheme 1, compound of formula 1 (commercially
available from Aldrich Chemical Co., [4746-97-8]) when treated with
tosylmethyl isocyanide (TOSMIC, commercially available from Aldrich
Chemical Co., [36635-61-7]) in the presence of a base such as
potassium tert-butoxide in a solvent such as ethylene glycol
dimethyl ether will provide the compound of formula 2. Compound of
formula 2 when treated with lithium aluminum hydride in THF will
provide the compound of formula 3. Compound of formula 3 when
treated with paraformaldehyde along with sulfuric acid in ethanol
will provide the compound of formula 4 (1-azaadamantan-4-one). A
further description of the synthesis may be found in Synthesis,
1992, 1080, Becker. D. P.; Flynn, D. L.
##STR00007##
[0200] As outlined in Scheme 2, compounds of formula 5, wherein
R.sup.x1, R.sup.x2, R.sup.x3, and R.sup.x4 are defined in formula
(I), and n is selected from 1, 2, and 3, when treated with a metal,
such as, but not limited to, lithium or magnesium, or an organic
metal reagent, such as, but not limited to, EtMgBr or .sup.tBuLi,
will provide compound of formula 6, wherein M is MgBr or Li.
Compounds of formula 6 when treated with azaadmantanone (4) in an
organic solvent, such as but not limited to Et.sub.2O, THF, or DME,
will provide compounds of formula 7 and 8, (r) and (s) isomers
respectively, which may be separated through chromatographic
methods as known to one skilled in the art. The individual isomers
or the mixture of both compounds of formula 7 and compounds of
formula 8 when further treated with a base, such as .sup.tBuOK or
KHMDS, will provide a Spiro ether of formula 9 and 10,
respectively. When a mixture of compounds of formula 7 and of
formula 8 are used, the individual, (s)-isomer of formula 9 and or
(r) isomer of formula 10 may be separated through chromatographic
methods that are known to one skilled in the art.
##STR00008##
[0201] As outlined in Scheme 3, compounds of formula 10, which may
be either the mixture or the individual isomers represented by the
compounds of formula 8 and 9, wherein n, R.sup.x1, R.sup.x2, and
R.sup.x4 are as defined in formula (I), when treated with
N-bromosuccinimide in presence an acid, such as, but not limited
to, acetic acid, in a solvent, for example acetonitrile, will
provide compounds of formula 11. Compounds of formula 11 when
treated with a hexamethylditin or an organo-boron compound of
formula 12, such as bis(pinacolato)diboron or
bis(eateeholato)diboron, wherein R.sup.m is hydrogen, alkyl, or
aryl, in the presence of a palladium catalyst, such as, but not
limited to, PdCl.sub.2(PPh.sub.3).sub.2 or PdCl.sub.2(dppf), will
provide the corresponding tin or boronic acid/esters of formula 13,
wherein M.sup.1 is --SnMe.sub.3 or --B(OR.sup.m).sub.2. Compounds
of formula 13 when treated with compounds of formula 14 wherein
R.sup.5 is an aryl or heteroaryl ring and halo is bromide,
chloride, or iodide, in the presence of a palladium catalyst, such
as, but not limited to, Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf), or Pd.sub.2(dba).sub.3, will
provide compounds of formula 15. Alternatively, compounds of
formula 11 when treated with compound of formula 16, wherein
R.sup.5 is an aryl or heteroaryl ring and M.sup.2 is --SnMe.sub.3
or --B(OR.sup.m).sub.2, which is either commercially available, or
prepared from compound of formula 14 by methods well-known to those
skilled in the art, in the presence of a palladium catalyst, such
as, but not limited to, Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf) or Pd.sub.2(dba).sub.3, will
provide compounds of formula 15. Compounds of formula 11 when
treated with compounds of formula 17, wherein R.sup.6 and R.sup.7
are each independently H, alkyl, aryl, alkoxylcarbonyl,
arylcarbonyl, cyclicalkyl, or heteroaryl, in the presence of a
ligand, such as, but not limited to, BINAP, Xantphos,
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine,
dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine, or
2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, and a
palladium catalyst, such as, but not limited to, Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4. PdCl.sub.2(dppf),
or Pd.sub.2(dba).sub.3, with a base, for example .sup.tBuONa or
Cs.sub.2CO.sub.3, in a solvent, such as, but not limited to,
toluene at 110.degree. C. as described in Org. Lett., 2005, 7,
3965, will provide compounds of formula 18. Compound of formula 11
when treated with an alcohol of formula 19, wherein R.sup.8 is
alkyl, in presence of a base, such as, but not limited to, NaH or
.sup.tBuOK, in an organic solvent such as, but not limited to, DMF
or THF, will provide compound of formula 20. Alternatively, when
compounds of formula 11 treated with compound of formula 19,
wherein R.sup.8 is an aryl group, in the presence of a copper
catalyst, such as, but not limited to, Cu, CuCl, or CuI, and a
ligand, such as, but not limited to,
2,2,6,6-tetramethylheptane-3,5-dione, and Cs.sub.2CO.sub.3 will
provide compounds of formula 20 as described in Org. Lett. 2002, 4,
1623. Compound of formula 11 when treated with an aqueous basic
solution, such as, but not limited to, NaOH or KOH, in the presence
of a copper catalyst, such as, but not limited to, copper, CuCl or
CuI, and an amino acid additive, such as, but not limited to,
L-pyrroline, at high temperature using microwave heating will
provide a compound of formula 21. Compounds of formula 21 when
treated with alkyl halide of formula 22, wherein R.sup.8 is alkyl,
and halo is chloro, bromo or iodo, in the presence of a base, such
as, but not limited to, Na.sub.2CO.sub.3, NaH, or NaHMDS, will
provide compounds of formula 20. On the other hand, compounds of
formula 21 when treated with an aryl halide of formula 22, wherein
R.sup.9 is aryl, and halo is chloro, bromo, or iodo, in the
presence of a copper catalyst, such as, but not limited to, Cu,
CuCl, or CuI, a ligand, such as, but not limited to,
2,2,6,6-tetramethylheptane-3,5-dione, and Cs.sub.2CO.sub.3 will
provide compound of formula 20.
##STR00009##
[0202] As shown in Scheme 4, compound of formula 4 when treated
with borane-THF complex in THF will provide the borane complexed
amine of formula 23, which when further treated with
trimethylsulfoxonium iodide in the presence of, but not limited to,
NaH will provide (rs) mixture of oxirane of formula 24. Compounds
of formula 25, wherein n, R.sup.x2, R.sup.x3, and R.sup.x4 are
previously defined and halo is bromo or iodo, when treated with
ter-butyl lithium or phenyl lithium, will provide compound of
formula 26, which when further treated with the compound of formula
24 will provide a (rs) mixture of compounds of formula 27. The (rs)
mixture of compounds of formula 27, when treated with a base, such
as, but not limited to, .sup.tBuOK or KHMDS, will provide either
(rs) mixture of the Spiro ether containing compounds of formula 28,
which may be separated using chromatographic methods known to one
skilled in the art. Alternatively, the (rs) mixture of compounds of
formula 27 may be separated using chromatographic methods to obtain
the individual (r) or (s) isomers which, when treated individually
with a base such as, but not limited to. .sup.tBuOK or KHMDS, will
provide either the individual (r) or (s) isomer of the spiro ether
containing compounds of formula 28.
##STR00010##
[0203] As outlined in Scheme 5, compounds of formula 29, which may
be either the (rs) mixture or the separated individual (r) or (s)
isomers, wherein n, R.sup.x2, and R.sup.x4 are as defined in
formula (I), when treated with reagents such as but not limited to
N-bromosuccinimide will provide compounds of formula 30. Compounds
of formula 30 when treated with hexamethylditin or an organo-boron
compound of formula 12, such as bis(pinacolato)diboron or
bis(catecholato)diboron, wherein R.sup.m is hydrogen, alkyl, or
aryl, in the presence of a palladium catalyst, such as but not
limited to PdCl.sub.2(PPh.sub.3).sub.2 or PdCl.sub.2(dppf), will
provide the corresponding tin or boronic acid/esters of formula 31,
wherein M is --SnMe.sub.3 or --B(OR.sup.m).sub.2. Compounds of
formula 31 when treated with compounds of formula 14, wherein
R.sup.5 is an aryl or heteroaryl and halo is bromide, chloride, or
iodide, in the presence of a palladium catalyst, such as, but not
limited to, Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf), or Pd.sub.2(dba).sub.3, will
provide compounds of formula 32. Alternatively, compounds of
formula 30 when treated with a compound of formula 16, wherein
R.sup.5 is an aryl or heteroaryl and M is --SnMe.sub.3 or
--B(OR.sup.m).sub.2 in the presence of a palladium catalyst, such
as, but not limited to, Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf), or Pd.sub.2(dba).sub.3, will
provide compounds of formula 32. Compounds of formula 30 when
treated with a compound of formula 17, wherein R.sup.6 and R.sup.7
are independently selected from H, alkyl, aryl, alkoxylcarbonyl,
arylcarbonyl, cyclic alkyl, and heteroaryl, in the presence of a
ligand, such as but not limited to BINAP. Xantphos,
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine,
dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine, or
2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, and a
palladium catalyst, for example Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf)
or Pd.sub.2(dba).sub.3, with a base, such as, but not limited to,
.sup.tBuONa or Cs.sub.2CO.sub.3 at 110.degree. C. as described in
Org. Lett., 2005, 7, 3965, will provide compounds of formula 33.
Compounds of formula 30 when treated with an alcohol of formula 19,
wherein R.sup.8 is alkyl, in presence of a base, such as, but not
limited to, NaH or .sup.tBuOK, in an organic solvent such as, but
not limited to, DMF or THF, will provide compounds of formula 34.
Alternatively, compounds of formula 30 when treated with a compound
of formula 19, wherein R.sup.8 is an aryl group, in the presence of
a copper catalyst, such as, but not limited to, Cu, CuCl or CuI,
and a ligand, such as, but not limited to,
2,2,6,6-tetramethylheptane-3,5-dione, and Cs.sub.2CO.sub.3 will
provide compounds of formula 34 as described in Org. Lett. 2002, 4,
1623. Alternatively, compounds of formula 30 when treated with an
aqueous basic solution, such as, but not limited to, NaOH or KOH,
in the presence of a copper catalyst, such as, but not limited to
copper, CuCl or CuI, and an amino acid additive, such as, but not
limited, to L-pyrroline, at high temperature using microwave
heating will provide compounds of formula 35. Compounds of formula
35 when treated with an alkyl halide of formula 22, wherein R.sup.9
is an alkyl and halo is chloro, bromo, or iodo, in the presence of
a base, such as, but not limited to, Na.sub.2CO.sub.3, NaH, or
NaHMDS, will provide compounds of formula 34. Alternatively,
compounds of 35 when treated with an aryl halide of formula 22,
wherein R.sup.9 is aryl and halo is bromo or iodo, in the presence
of a copper catalyst, such as, but not limited to, Cu, CuCl or CuI,
and a ligand, such as, but not limited to,
2,2,6,6-tetramethylheptane-3,5-dione, and Cs.sub.2CO.sub.3 will
provide compounds of formula 34.
##STR00011##
[0204] As outlined in Scheme 6, compounds of formula 36, which may
be either the (rs) mixture or the separated individual (r) or (s)
isomers, wherein n, R.sup.x3, and R.sup.x4 are as defined in
formula (I), when treated with m-chloroperbenzoic acid in an
organic solvent, such as, but not limited to, dichlormethane or
acetonitrile, will provide compounds of formula 37. Compounds of
formula 37 when treated with POCl.sub.3, which can be heated to
facilitate the reaction, will provide compounds of formula 38.
Compounds of formula 38 when treated with a compound of formula 16
wherein R.sup.5 is aryl or heteroaryl and M is --SnMe.sub.3 or
--B(OR.sup.m).sub.2 in the presence of a palladium catalyst, such
as, but not limited to, Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf), or Pd.sub.2(dba).sub.3, will
provide compounds of formula 39. Alternatively, when compounds of
formula 38 when treated with a compound of formula 17, wherein
R.sup.6 and R.sup.7 are as previously defined, in the presence of a
ligand, such as, but not limited to, BINAP, Xantphos,
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine,
dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine, or
2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, and a
palladium catalyst, such as, but not limited to, Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf),
or Pd.sub.2(dba).sub.3, with a base, such as, but not limited to,
.sup.tBuONa or Cs.sub.2CO.sub.3 at 110.degree. C. as described in
Org. Lett., 2005, 7, 3965, will provide compounds of formula 40.
Compounds of formula 38 when treated with an alcohol of formula 19,
wherein R.sup.8 is as previously defined, in presence of a base,
such as, but not limited to, NaH or .sup.tBuOK, will provide
compounds of formula 41.
##STR00012##
[0205] As outlined in Scheme 6, compounds of formula 42, wherein n,
R.sup.x1, R.sup.x3, and R.sup.x4 are defined in formula (I), when
treated with a metal, such as magnesium, or an organometallic
reagent, such as but not limited to EtMgBr or .sup.tBuLi, will
provide compounds of formula 43, wherein M is MgBr or Li. Compounds
of formula 43 when further treated with the compound of formula 4
(azaadmantanone) will provide the (rs)-mixture of isomers of
compounds of formula 44. Compounds of formula 44 when treated with
a base, such as .sup.tBuOK or KHMDS, will provide the (rs) mixture
of spiro ether containing compounds of formula 45. The individual,
(r)- and (s)-isomers of compounds of formula 45 may be separated by
chromatographic methods as known by one skilled in the art.
##STR00013##
[0206] As outlined in Scheme 8, compounds of formula 46, which may
be either the (rs) mixture or the separated individual (r)- or
(s)-isomers, wherein n, R.sup.x1, and R.sup.x4 are as defined in
formula (I), when treated with N-bromosuccinimide will provide
compounds of formula 47. Compounds of formula 47 when treated with
compounds of formula 16 wherein R.sup.5 and M are as defined in
Scheme 3, in the presence of a palladium catalyst, such as, but not
limited to, Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf), or Pd.sub.2(dba).sub.3, will
provide compounds of formula 48. Compounds of formula 47 when
treated with a compound of formula 17, wherein R.sup.6 and R.sup.7
are as defined in Scheme 3, in the presence of a ligand, such as,
but not limited to, BINAP, Xantphos,
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine,
dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine, or
2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, and a
palladium catalyst, such as, but not limited to, Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf),
or Pd.sub.2(dba).sub.3, and a base, such as, but not limited to,
.sup.tBuONa or Cs.sub.2CO.sub.3, at 110.degree. C. as described in
Org. Lett., 2005, 7, 3965, will provide compounds of formula 50.
Compounds of formula 47 when treated with a compound of formula 19,
wherein R.sup.8 is as defined in Scheme 3, in presence of a base,
such as, but not limited to, NaH or .sup.tBuOK, will provide
compounds of formula 51.
##STR00014##
[0207] As outlined in Scheme 9, compounds of formula 52, wherein n,
X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are as defined in formula
(I), and X is chloro or bromo, when treated with will provide
compounds of formula 53. Compounds of formula 23 when treated with
compounds of formula 54, wherein R.sup.b is as defined in formula
(I), will provide compounds of formula 55. Compounds of formula 55
when is further treated with a compound of formula 53, will provide
compounds of formula 56. Compounds of formula 56 will cyclize to
provide compound of formula 57, in the presence of a palladium
catalyst, such as, but not limited to, Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf),
or Pd.sub.2(dba).sub.3, a ligand, such as but not limited to BINAP,
Xantphos,
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine,
dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine, or
2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, and a
base, such as but not limited to .sup.tBuONa or Cs.sub.2CO.sub.3 at
110.degree. C. as described in Org. Lett., 2005, 7, 3965.
##STR00015##
[0208] As outlined in Scheme 10, compounds of formula 58, which may
be either the (rs) mixture or the separated individual (r) or (s)
isomers, wherein n, R.sup.b, X.sup.1, X.sup.2, and X.sup.4.sub.4
are as defined in formula (I), when treated with N-bromosuccinimide
will provide compound of formula 59. Compound of formula 59 when
treated with hexamethylditin, or an organo-boron compound of
formula 12, in the presence of a palladium catalyst, such as, but
not limited to, PdCl.sub.2(PPh.sub.3).sub.2 or PdCl.sub.2(dppf),
will provide the corresponding tin or boronic acid/esters of
formula 60, wherein M is --SnMe.sub.3 or --B(OR.sup.m).sub.2.
Compounds of formula 60 when treated with compounds of formula 14
wherein R.sup.5 and halo are as defined in Scheme 7, in the
presence of a palladium catalyst, such as but not limited to
Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4,
PdCl.sub.2(dppf) or Pd.sub.2(dba).sub.3, will provide compounds of
formula 61. Alternatively, compounds of formula 59 when treated
with compound of formula 16, described in Scheme 3, in the presence
of a palladium catalyst, such as but not limited to, Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf),
or Pd.sub.2(dba).sub.3, will provide compounds of formula 61.
Compound of formula 59 when treated with compound of formula 17,
wherein R.sup.6 and R.sup.7 are as defined in Scheme 3, in the
presence of a ligand, such as but not limited to BINAP, Xantphos,
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine,
dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine, or
2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, and a
palladium catalyst, such as, but not limited to, Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4. PdCl.sub.2(dppf),
or Pd.sub.2(dba).sub.3, and a base, such as, but not limited to,
.sup.tBuONa or Cs.sub.2CO.sub.3 at 110.degree. C. as described in
Org. Lett., 2005, 7, 3965, will provide compounds of formula 62.
Compound of formula 59 when treated with the compound of formula
19, wherein R.sup.8 is as described in Scheme 3, according to the
method described in Scheme 3, will provide compound of formula
63.
##STR00016##
[0209] As shown in Scheme 11, the compound of formula 64, wherein
L.sup.3 and L.sup.4 are each independently selected from group
consisting of O and NR.sup.b, and R.sup.b, X.sup.1, X.sup.2,
X.sup.3, and X.sup.4 are as defined in formula (I), when treated
with compound of formula 4, in the presence of an acid, such as but
not limited to p-toluenesulfonic acid, will provide compound of
formula 65.
##STR00017##
[0210] As shown in Scheme 12, the compound of formula 66, wherein
R.sup.b, X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are as defined in
formula (I), when treated with compound of formula 4, in the
presence of an acid, such as but not limited to p-toluenesulfonic
acid, will provide compound of formula 67.
[0211] In addition, compounds of formula (II), (III), and (IV) may
be converted to an N-oxide compounds of formula (I) 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.
[0212] 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.
[0213] The compounds of the invention contain 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 treated 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.
[0214] The compounds of the invention and processes for making
compounds for the method 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.
EXAMPLES
Example 1
3H-(4's)-1'-Azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
bis(hydrochloric acid)
Example 1A
(4s)- and
(4r)-4-(2-Fluorobenzyl)-1-azatricyclo[3.3.1.1.sup.3,7]decan-4-ol
[0215] Magnesium turning (Aldrich, 2.40 g, 0.1 mol) and I.sub.2
(Aldrich, 10 mg) were combined in diethyl ether (Aldrich,
anhydrous, 20 mL) and treated with 1-(bromomethyl)-2-fluorobenzene
(Aldrich, 18.9 g, 0.1 mol) in diethyl ether (Aldrich, anhydrous,
200 mL) at ambient temperature under N.sub.2. After the reaction
was initiated (discharge of iodine brown color), the addition of
1-(bromomethyl)-2-fluorobenzene ether solution was continued to
maintain the reaction temperature .ltoreq.30.degree. C. After the
addition was completed, the mixture was stirred at ambient
temperature for 4 h. 1-Azatricyclo[3.3.1.1 3,7]decan-4-one (ref.
Synthesis, 1992, 1080-1082, 7.60 g, 50 mmol) in diethyl ether
(Aldrich, anhydrous, 50 mL) was added at 0-5.degree. C. The
reaction mixture was then stirred at ambient temperature for 10 h.
It was then quenched with saturated NH.sub.4Cl (20 mL) at
5-10.degree. C. and extracted with CHCl.sub.3 (3.times.100 mL). The
combined extracts were concentrated and the residue was purified
with chromatography (SiO.sub.2, CHCl.sub.3/MeOH (with 2 v. %
NH.sub.3.H.sub.2O)=90/10). The upper spot (R.sub.f=0.25) was
isolated (4.71 g, yield, 36.1%) and confirmed as (4s)-stereoisomer
of the title compound. The lower spot (R.sub.f=0.10) was obtained
(3.33 g, yield, 17.9%) and confirmed as (40-stereoisomer of the
title compound.
(4s)-4-(2-Fluorobenzyl)-1-azatricyclo[3.3.1.1.sup.3,7]decan-4-ol:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 1.50-1.63 (m, 3H),
1.68-1.84 (m, 2H), 2.33-2.53 (m, 2H), 3.05-3.11 (m, 4H), 3.16 (d,
J=13.90 Hz, 2H), 3.43 (d, J=13.56 Hz, 2H), 6.97-7.07 (m, 1H), 7.10
(dd, J=7.46, 1.02 Hz, 1H), 7.17-7.28 (m, 1H), 7.35 (td, J=7.63,
1.70 Hz, 1H): MS (DCI/NH.sub.3) m/z=262 (M+H).sup.+;
(4r)-4-(2-Fluorobenzyl)-1-azatricyclo[3.3.1.1.sup.3,7]decan-4-ol:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 1.47-1.64 (m, 2H),
1.66-1.80 (m, 1H), 1.96-2.12 (m, 2H), 2.26-2.45 (m, 2H), 2.86 (d,
J=12.55 Hz, 2H), 3.02-3.14 (m, 4H), 3.54 (d, J=12.55 Hz, 2H),
6.98-7.04 (m, 1H), 7.08 (td, J=7.46, 1.36 Hz, 1H), 7.17-7.27 (m,
1H), 7.35 (td, J=7.54, 1.86 Hz, 1H); MS (DCI/NH.sub.3) m/z=262
(M+H).sup.+.
Example 1B
3H-(4's)-1'-Azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
[0216] The (4s)-stereoisomer of Example 1A (4.50 g, 17.2 mmol) was
treated with .sup.tBuOK (Aldrich, 2.24 g, 20 mmol) in THF (Aldrich,
anhydrous, 100 mL) at 65.degree. C. for 50 h. It was then cooled
down to ambient temperature and quenched with water (10 mL). The
reaction mixture was extracted with CHCl.sub.3 (3.times.100 mL).
The combined extracts were concentrated and the residue was
purified with chromatography (SiO.sub.2, CHCl.sub.3/MeOH (with 2 v.
% NH.sub.3.H.sub.2O)=90/10, R.sub.f=0.20) to give the title
compound (3.34 g, yield, 80.6%). .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 1.46-1.59 (m, 1H), 1.63-1.73 (m, 2H),
1.74-1.90 (m, 2H), 2.25-2.40 (m, 2H), 2.93-3.15 (m, 7H), 3.27-3.29
(m, 1H), 6.71-6.82 (m, 2H), 7.06 (td, J=7.71, 1.53 Hz, 1H), 7.16
(dd, J=7.12, 1.02 Hz, 1H); MS (DCI/NH.sub.3) m/z=242
(M+H).sup.+.
Example 1C
3H-(4's)-1'-Azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
bis(hydrochloric acid)
[0217] The product of Example 1B (80 mg, 0.33 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.2 mL, 0.8 mmol) in EtOAc (5
mL) at ambient temperature for 10 h to give the title compound (75
mg, yield, 72.8%). .sup.1NMR (300 MHz, CD.sub.3OD) .delta. ppm 1.98
(d, J=13.22 Hz, 2H), 2.12-2.29 (m, 3H), 2.54 (d, J=13.22 Hz, 2H),
3.27-3.30 (m, 2 H), 3.55-3.60 (m, 2H), 3.61-3.68 (m, 4H), 6.79 (d,
J=7.80 Hz, 1H), 6.85 (t, J=7.46 Hz, 1H), 7.11 (t, J=7.12 Hz, 1H),
7.19 (d, J=7.46 Hz, 1H); MS (DCI/NH.sub.3) m/z=242 (M+H).sup.+.
Anal. Calc. for C.sub.16H.sub.19NO.1.89HCl: C, 61.94; H, 6.79; N,
4.51. Found: C, 61.54; H, 6.64; N, 4.32.
Example 2
3H-(4's)-1'-Azaspiro
5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
hydrochloric acid
Example 2A
3H-(4's)-1'-Azaspiro[5-bromobenzofuran-2,4]-tricyclo[3.3.1.1.sup.3,7]decan-
e
[0218] The product of Example 1B (2.07 g, 8.6 mmol) was treated
with N-bromosuccinimide (NBS) (Aldrch, 2.30 g, 12.9 mmol) in
MeCN/HOAc (v. 5/1, 70 mL) at 0.degree. C. to ambient temperature
for 6 h. After the reaction was completed, it was quenched with
water (5.0 mL) and concentrated. The residue was basified with
saturated Na.sub.2CO.sub.3 until pH=9-10. The mixture was then
extracted with CHCl.sub.3 (3.times.50 mL). The combined extracts
were concentrated and the residue was purified with chromatography
(SiO.sub.2, CHCl.sub.3/MeOH (with 2 v. % NH.sub.3.H.sub.2O)=90/10,
R.sub.f=0.25) to give the title compound (2.50 g, yield, 90.8%).
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.56-1.73 (m, 1H),
1.77-1.84 (m, 2H), 1.85-1.98 (m, 2H), 2.33-2.59 (m, 2H), 3.02-3.26
(m, 8H), 6.66 (d, J=8.48 Hz, 1H), 7.18 (dd, J=8.48, 2.37 Hz, 1H),
7.29 (d, J=2.03 Hz, 1H); MS (DCI/NH.sub.3) m/z=320 (M+H).sup.+, 322
(M+H).sup.+.
Example 2B
3H-(4's)-1'-Azaspiro[5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]deca-
ne hydrochloric acid
[0219] The product of Example 2A (80 mg, 0.25 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.2 mL, 0.8 mmol) in EtOAc (5
mL) at ambient temperature for 10 h to give the title compound (60
mg, yield, 67.3%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm
1.87-2.06 (m, 2H), 2.12-2.34 (m, 3H), 2.39-2.63 (m, 2H), 3.26-3.39
(m, 2H), 3.52-3.60 (m, 2H), 3.59-3.75 (m, 4H), 6.73 (d, J=8.48 Hz,
1H), 7.25 (dd, J=8.48, 2.37 Hz, 1H), 7.34 (d, J=2.03 Hz, 1H); MS
(DCI/NH.sub.3) m/z=320 (M+H).sup.+, 322 (M+H).sup.+. Anal. Calc.
for C.sub.16H.sub.18BrNO.1.00HCl.0.20H.sub.2O: C, 53.34; H, 5.34;
N, 3.89. Found: C, 53.22; H, 5.30; N, 3.79.
Example 3
3H-(4's)-1'-Azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]dec-
ane hydrochloric acid
Example 3A
3H-(4's)-1'-Azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]dec-
ane
[0220] The product of Example 2A (200.0 mg 0.625 mmol) was coupled
with phenyl-boronic acid (Aldrich, 113 mg, 0.94 mmol) under the
catalysis of Pd(PPh.sub.3).sub.4 (Aldrich, 14.4 mg, 0.0125 mmol) in
1,4-dioxane (5.0 mL) and K.sub.2CO.sub.3 (2M, 1 mL) at 90.degree.
C. for 3 h. Upon completion of the reaction, the mixture was
diluted with CHCl.sub.3 (10 mL), washed with brine (2.times.2 mL),
the organic solution was concentrated. The residue was purified by
preparative HPLC [Waters.RTM. XTerra RP18 column, 5.mu..
30.times.100 mm, flow rate 40 mL/minute, 5-95% gradient of
acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate,
adjusted to pH 10 with ammonium hydroxide), with UV detection at
254 nm]. Fractions containing the desired product were pooled,
concentrated under vacuum, diluted with methanol or ethyl acetate,
and filtered to afford the title compound (80 mg, yield, 41%).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 1.63-1.78 (m, 1H),
1.79-1.99 (m, 4H), 2.38-2.68 (m, 2H), 3.07-3.27 (m, 8H), 6.80 (d,
J=8.14 Hz, 1H), 7.19-7.28 (m, 1H), 7.30-7.45 (m, 4H), 7.48-7.61 (m,
2H): MS (DCI/NH.sub.3) m/z=318 (M+H).sup.+.
Example 3B
3H-(4's)-1'-Azaspiro[5-phenylbenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]dec-
ane hydrochloric acid
[0221] The product of Example 3A (80 mg, 0.25 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.1 mL, 0.4 mmol) in EtOAc (5
mL) at ambient temperature for 10 h to give the title compound (85
mg, yield, 87.6%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm
1.87-2.06 (m, 2H), 2.12-2.34 (m, 3H), 2.39-2.63 (m, 2H), 3.26-3.39
(m, 2H), 3.52-3.60 (m, 2H), 3.59-3.75 (m, 4H), 6.73 (d, J=8.48 Hz,
1H), 7.25 (dd, J=8.48, 2.37 Hz, 1H), 7.34 (d, J=2.03 Hz, 1H); MS
(DCI/NH.sub.3) m/z=318 (M+H).sup.+. Anal. Calc. for
C.sub.22H.sub.23NO.1.25HCl: C, 72.79; H, 6.73; N, 3.86. Found: C,
72.55; H, 6.68; N, 3.66.
Example 4
3H-(4's)-1'-Azaspiro[5-(indol-5-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane
[0222] The product of Example 2A (200.0 mg 0.625 mmol) was coupled
with indol-5-yl boronic acid (Frontier, 150 mg, 0.94 mmol)
according to the procedure of Example 3A to give the title compound
(110 mg, yield, 49.4%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
ppm 1.87-2.08 (m, 3H), 2.08-2.22 (m, 2H), 2.41-2.69 (m, 2H),
3.33-3.36 (m, 2H), 3.39-3.52 (m, 6H), 6.45 (dd, J=3.05, 0.68 Hz,
1H), 6.82 (d, J=8.14 Hz, 1H), 7.23 (d, J=3.05 Hz, 1H), 7.28 (dd,
J=8.50, 1.70 Hz, 1H), 7.34-7.44 (m, 2H), 7.45 (s, 1H), 7.67 (d,
J=1.70 Hz, 1H): MS (DCI/NH.sub.3) m/z=357 (M+H).sup.+.
Example 5
3H-(4's)-1'-Azaspiro[5-(indol-6-yl)-benzofuran-2,4]-tricyclo[3.3.1.1.sup.3-
,7]decane
[0223] The product of Example 2A (300 mg, 0.98 mmol) was coupled
with indol-6-yl boronic acid (Frontier, 300 mg, 1.86 mmol)
according to the procedure of Example 3A to give the title compound
solid (17.3 mg, yield, 4.9%). .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. ppm 1.57-1.79 (m, 1H), 1.82-2.04 (m, 4H), 2.29-2.65 (m,
2H), 3.11-3.28 (m, 8H), 6.42 (dd, J=3.05, 0.68 Hz, 1H), 6.79 (d,
J=8.48 Hz, 1H), 7.16-7.25 (m, 2H), 7.37 (dd, J=8.14, 2.03 Hz, 1H),
7.45 (s, 1H), 7.51 (s, 1H), 7.54 (d, J=8.48 Hz, 1H): MS
(DCI/NH.sub.3) m/z 357 (M+1).sup.+.
Example 6
3H-(4's)-1'-Azaspiro[5-(indol-4-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane trifluoroacetate
[0224] The product of Example 2A (200 mg, 0.625 mmol) was coupled
with indolyl-4-boronic acid (150 mg, 0.94 mmol: Frontier) under the
catalysis of PdCl.sub.2(PPh.sub.3).sub.2 (Aldrich, 7.0 mg, 0.01
mmol.) and biphenyl-2-yl-dicyclohexyl-phosphane (Aldrich, 10.5 mg,
0.03 mmol) in dioxane/EtOH/Na.sub.2CO.sub.3 (aq., 1 M) (v. 1/1/1, 3
mL) at 150.degree. C. (150 watts max.) for 15 min in an Emry.TM.
Creator microwave. The inorganic solid was filtered off with a
syringe filter and the liquid mixture was purified by preparative
HPLC (Gilson, column, Xterra.RTM. 5 .mu.m, 40.times.100 mm; eluting
Solvent, MeCN/H.sub.2O (with 0.1v. % TFA) (v. 90/10 to 10/90 over
25 min.); flow rate, 40 mL/min. uv, 254 nm), fractions of the
desired product were collected and concentrated, the residue was
stirred in Et.sub.2O/EtOH (v. 10/1, 5 mL) for 16 h, to give the
title compound as solid (13.5 mg, yield, 4.2%). .sup.1H NMR (300
MHz, DMSO-D.sub.6) .delta. ppm 1.79-2.01 (m, 2H), 2.07-2.18 (m,
1H), 2.19-2.38 (m, 4H), 3.34-3.40 (m, 2H), 3.43-3.68 (m, 6H),
6.48-6.59 (m, 1H), 6.93 (d, J=8.14 Hz, 1H), 6.99 (dd, J=7.12, 1.02
Hz, 1H), 7.14 (t, J=7.10 Hz, 1H), 7.33-7.39 (m, 2H), 7.42 (dd,
J=8.31, 1.86 Hz, 1H), 7.47 (s, 1H), 11.2 (s, 1H); MS (DCI/NH.sub.3)
m/z 357 (M+1).sup.+; Anal. calcd. for
C.sub.24H.sub.24N.sub.2O.1.20CF.sub.3CO.sub.2H: C, 64.28; H, 5.15;
N, 5.68. Found: C, 64.52; H, 4.90; N, 5.81.
Example 7
3H-(4'r)-1'-Azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
hydrochloric acid
Example 7A
3H-(4'r)-1'-Azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
[0225] Prepared from the (4r)-stereoisomer of Example 1A (3.11 g,
11.9 mmol) and .sup.tBuOK (Aldrich, 1.68 g, 15 mmol) according to
the procedure of Example 1B (1.23 g, yield, 42.9%). .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 1.49-1.61 (m, 1H), 1.61-1.73
(m, 2H), 1.89-2.07 (m, 4H), 2.85-2.90 (m, 1H), 2.90-2.94 (m, 1H),
2.95-3.00 (m, 2H), 3.12-3.15 (m, 2H), 3.34-3.43 (m, 2H), 6.73-6.80
(m, 2H), 7.06 (td. J=7.80, 1.36 Hz, 1H), 7.17 (d, J=7.12 Hz, 1H);
MS (DCI/NH.sub.3) m/z=242 (M+14).sup.+.
Example 7B
3H-(4'r)-1'-Azaspiro[benzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]decane
hydrochloric acid
[0226] The product of Example 1B (80 mg, 0.33 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.2 mL, 0.8 mmol) in EtOAc (5
mL) at ambient temperature for 10 h to give the title compound (70
mg, yield, 76.4%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm
2.04-2.39 (m, 7H), 3.30-3.35 (m, 2H), 3.45-3.69 (m, 4H), 3.93 (d,
J=11.87 Hz, 2H), 6.78 (d, J=8.14 Hz, 1H), 6.86 (td, J=7.46, 1.02
Hz, 1H), 7.11 (td, J=7.97, 1.02 Hz, 1H), 7.21 (dd, J=7.46, 1.02 Hz,
1H); MS (DCI/NH.sub.3) m/z=242 (M+H), Anal. Calc. for
C.sub.16H.sub.19NO.1.00HCl.0.10H.sub.2O: C, 68.73; H, 7.28; N,
5.01. Found: C, 68.67; H, 7.23; N, 4.92.
Example 8
3H-(4'r)-1'-Azaspiro[5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]deca-
ne hydrochloric acid
Example 8A
3H-(4'r)-1'-Azaspiro[5-bromobenzofuran-2,4]-tricyclo[3.3.1.1.sup.3,7]decan-
e
[0227] Prepared from the product of Example 7A (1.20 g, 5.0 mmol)
and N-bromosuccinimide (NBS) (Aldrch, 1.34, 7.5 mmol) according to
the procedure of Example 2A (1.25 g, yield, 78.1%). .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 1.63-1.74 (m, 1H), 1.76-1.85
(m, 2H), 1.96-2.19 (m, 4H), 3.03 (d, J=12.89 Hz, 2H), 3.09-3.16 (m,
2H), 3.18-3.24 (m, 2H), 3.56 (d, J=12.55 Hz, 2H), 6.66 (d, J=8.48
Hz, 1H), 7.18 (dd, J=8.48, 2.03 Hz, 1H), 7.27-7.30 (m, 1H); MS
(DCI/NH.sub.3) m/z=320 (M+H).sup.+, 322 (M+H).sup.+.
Example 8B
3H-(4'r)-1'-Azaspiro[5-bromobenzofuran-2,4']-tricyclo[3.3.1.1.sup.3,7]deca-
ne hydrochloric acid
[0228] The product of Example 8A (70 mg, 0.22 mmol) was treated
with HCl (Aldrich, 4 M in dioxane, 0.1 mL, 0.4 mmol) in EtOAc (5
mL) at ambient temperature for 10 h to give the title compound (60
mg, yield, 76.5%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm
2.02-2.40 (m, 7H), 3.32-3.34 (m, 2H), 3.50 (d, J=12.55 Hz, 2H),
3.54-3.58 (m, 2H), 3.91 (d, J=11.87 Hz, 2H), 6.73 (d, J=8.48 Hz,
1H), 7.25 (dd, J=8.48, 2.03 Hz, 1H), 7.33-7.41 (m, 1H); MS
(DCI/NH.sub.3) m/z=320 (M+H).sup.+, 322 (M+H).sup.+. Anal. Calc.
for C.sub.16H.sub.18BrNO.1.00HCl.0.50H.sub.2O: C, 52.554; H, 5.51;
N, 3.83. Found: C, 52.21; 14, 5.490; N, 3.61.
Example 9
3H-(4'r)-1'-Azaspiro[5-phenylbenzofuran-2,4]'-tricyclo[3.3.1.1.sup.3,7]dec-
ane
[0229] Prepared from the product of Example 7A (160 mg 0.50 mmol)
and phenyl-boronic acid (Aldrich, 91 mg, 0.75 mmol) according to
the procedure of Example 3A (110 mg, yield, 69.3%). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. ppm 1.80-1.91 (m, 2H), 1.91-1.99 (m,
2H), 2.03-2.22 (m, 4H), 3.17 (d, J=12.54 Hz, 1H), 3.24-3.27 (m,
2H), 3.28-3.29 (m, 2H), 3.71 (d, J=12.54 Hz, 2H), 6.82 (d, J=8.14
Hz, 1H), 7.20-7.30 (m, 1H), 7.32-7.41 (m, 3H), 7.42-7.46 (m, 1H),
7.48-7.56 (m, 2H); MS (DCI/NH.sub.3) m/z=318 (M+H).sup.+.
Example 10
3H-(4'r)-1'-Azaspiro[5-(indol-5-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane
[0230] Prepared from the product of Example 7A (160 mg 0.50 mmol)
and indol-5-yl-boronic acid (Aldrich, 121 mg, 0.75 mmol) according
to the procedure of Example 3A (170 mg, yield, 95.0%). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. ppm 2.05-2.27 (m, 7H), 3.32-3.36 (m,
2H), 3.43 (d, J=12.21 Hz, 2H), 3.47-3.54 (m, 2H), 3.90 (d, J=12.54
Hz, 2H), 6.45 (dd, J=3.05, 0.68 Hz, 1H), 6.83 (d, J=8.48 Hz, 1H),
7.23 (d, J=3.05 Hz, 1H), 7.28 (dd, J=8.50, 1.70. Hz, 1H), 7.34-7.42
(m, 2H), 7.47 (d, J=1.36 Hz, 1H), 7.66-7.69 (m, 1H); MS
(DCI/NH.sub.3) m/z=357 (M+H).sup.+.
Example 11
3H-(4'r)-1'-Azaspiro[5-(benzo[b]thiophen-5-yl)-benzofuran-2,4']-tricyclo[3-
.3.1.1.sup.3,7]decane
[0231] Prepared from the product of Example 7A (160 mg 0.50 mmol)
and
2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Maybridge, 195 mg, 0.75 mmol) according to the procedure of
Example 3A (140 mg, yield, 75.0%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. ppm 2.10-2.21 (m, 7H), 3.36-3.39 (m, 2H), 3.44
(d, J=12.54 Hz, 2 H), 3.47-3.53 (m, 2H), 3.90 (d, J=11.87 Hz, 2H),
6.88 (d, J=8.48 Hz, 1H), 7.40 (d, J=5.42 Hz, 1H), 7.45 (dd, J=8.48,
2.03 Hz, 1H), 7.51-7.56 (m, 2H), 7.57 (d, J=5.76 Hz, 1H), 7.91 (d,
J=8.48 Hz, 1H), 7.98 (d, J=1.36 Hz, 1H); MS (DCI/NH.sub.3) m/z=374
(M+H).sup.+.
Example 12
3H-(4'r)-1'-Azaspiro[5-(indol-4-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.sup.-
3,7]decane
[0232] Prepared from the product of Example 7A (160 mg 0.50 mmol)
and indol-4-yl boronic acid (Frontier, 121 mg, 0.75 mmol) according
to the procedure of Example 3A (100 mg, yield, 56.0%). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. ppm 2.04-2.46 (m, 7H), 3.37-3.41 (m,
2H), 3.43-3.59 (m, 4H), 3.94 (d, J=12.21 Hz, 2H), 6.55 (dd, J=3.22,
0.85 Hz, 1H), 6.89 (d, J=8.14 Hz, 1H), 6.99 (dd, J=7.40, 10.85 Hz,
1H), 7.13 (dd, J=8.20, 7.40 Hz, 1H), 7.25 (d, J=3.05 Hz, 1H), 7.33
(dt, J=8.14, 1.02 Hz, 1H), 7.44 (dd, J=8.31, 1.86 Hz, 1H), 7.52 (d,
J=1.36 Hz, 1H): MS (DCI/NH.sub.3) m/z=357 (M+H).sup.+.
Example 13
3H-(4'r)-1'-Azaspiro[5-(2-oxo-indolin-5-yl)-benzofuran-2,4']-tricyclo[3.3.-
1.1.sup.3,7]decane
[0233] Prepared from the product of Example 7A (160 mg 0.50 mmol)
and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one
(ref. WO 2006065233, 194 mg, 0.75 mmol) according to the procedure
of Example 3A (120 mg, yield, 64.4%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. ppm 1.65-1.76 (m, 1H), 1.79-1.87 (m, 2H),
1.99-2.24 (m, 4H), 3.05 (d, J=12.89 Hz, 2H), 3.12-3.16 (m, 2H),
3.23-3.26 (m, 2H), 3.34 (s, 2H), 3.62 (d, J=12.55 Hz, 2H), 6.78 (d,
J=8.14 Hz, 1H), 6.91 (d, J=7.46 Hz, 1H), 7.28 (dd, J=8.48, 2.03 Hz,
1H), 7.37-7.40 (m, 2H), 7.43 (d, J=1.36 Hz, 1H); MS (DCI/NH.sub.3)
m/z=373 (M+H).sup.+.
Example 14
3H-(4'r)-1'-Azaspiro[5-(thiophen-3-yl)-benzofuran-2,4']-tricyclo[3.3.1.1.s-
up.3,7]decane
[0234] Prepared from the product of Example 7A (160 mg 0.50 mmol)
and thiophen-3-yl boronic acid (Aldrich, 96 mg, 0.75 mmol)
according to the procedure of Example 3A (160 mg, yield, 99.0%).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 2.05-2.40 (m, 7H),
3.35 (s, 2H), 3.49 (d, J=12.89 Hz, 2H), 3.53-3.61 (m, 2H), 3.92 (d,
J=12.21 Hz, 2H), 6.82 (d, J=8.48 Hz, 1H), 7.36 (dd, J=5.10, 1.30
Hz, 1H), 7.40-7.46 (m, 3H) 7.51 (d, J=1.36 Hz, 1H); MS
(DCI/NH.sub.3) m/z=324 (M+H).sup.+.
Example 15
3H-(4'r)-1'-Azaspiro[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzofuran-2,4']-tr-
icyclo[3.3.1.1.sup.3,7]decane
Example 15A
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
[0235] 5-Bromo-1H-pyrrolo[2,3-b]pyridine (Alfa Aesar, 1.00 g, 5.0
mmol) was coupled with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(Aldrich, 1.52 g, 6.0 mmol) under the catalysis of
{1,1'-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II)
dichloromethane complex PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (Aldrich,
82 mg, 0.1 mmol) with KOAc (Aldrich, 0.98 g, 10.0 mmol) in dioxane
(anhydrous, 20 mL) at 80.degree. C. for 10 h. It was then cooled
down to ambient temperature, concentrated and diluted with EtOAc
(100 mL). The mixture was then washed with brine (2.times.10 mL).
The organic solution was concentrated and the residue was purified
chromatography (SiO.sub.2, EtOAc/hexane, v. 50/50, R.sub.f0.40) to
give the title compound (1.15 g, yield, 94.2%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. ppm 1.38 (s, 12H) 6.52 (d, J=3.39 Hz, 1H)
7.38 (d, J=3.39 Hz, 1H) 8.34 (d, J=1.70 Hz, 1H) 8.49 (d, J=1.36 Hz,
1H); MS (DCI/NH.sub.3) m/z 245 (M+1).sup.+.
Example 15B
3H-(4'r)-1'-Azaspiro[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzofuran-2,4']-tr-
icyclo[3.3.1.1.sup.3,7]decane
[0236] Prepared from the products of Example 7A (160 mg 0.50 mmol)
and Example 15A (183 mg, 0.75 mmol) according to the procedure of
Example 3A (150 mg, yield, 84.0%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. ppm 2.10-2.31 (m, 7H), 3.39 (s, 2H), 3.48 (d,
J=12.55 Hz, 2H), 3.52-3.60 (m, 2H), 3.94 (d, J=12.21 Hz, 2H), 6.52
(d, J=3.73 Hz, 1H), 6.90 (d, J=8.48 Hz, 1H), 7.38-7.44 (m, 2H),
7.51 (d, J=1.36 Hz, 1H), 8.12 (d, J=2.03 Hz, 1H), 8.35 (d, J=2.37
Hz, 1H): MS (DCI/NH.sub.3) m/z=358 (M+H).sup.+.
Example 16
3H-(4'r)-1'-Azaspiro[5-(thieno[2,3-b]pyridin-5-yl)-benzofuran-2,4']-tricyc-
lo[3.3.1.1.sup.3,7]decane
Example 16A
1-(Thieno[2,3-b]pyridin-5-yl)ethanone
[0237] To a vigorously stirred mixture of 2-nitrothiophene
(Aldrich, 12.9 g, 0.1 mol) in concentrated HCl (Aldrich, 36.5%, 195
mL) was carefully added tin (Aldrich, 100 mesh, 25 g, 0.21 mol) at
20-30.degree. C. After most of tin metal had been dissolved, EtOH
(Aldrich, 70 mL) and ZnCl.sub.2 (Aldrich, 6.0 g, 0.044 mol) were
added and the mixture was then heated to 75.degree. C. for 1 h. The
brown solution was cooled down to ambient temperature and
4,4-dimethoxybutan-2-one (Aldrich, 39.6 g, 0.3 mol) in EtOH (50 mL)
was added. The reaction mixture was stirred at 70.degree. C. for 10
h. The cooled brown reaction mixture was poured into NaOH aqueous
solution (50%, 160 mL) and extracted with EtOAc (3.times.500 mL).
The combined extracts were washed with brine (2.times.50 mL) and
concentrated. The residue was purified with chromatography
(SiO.sub.2, EtOAc/hexane, v. 20/80, R.sub.f=0.30) to give the title
compound (4.20 g, yield, 23%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. ppm 2.72 (s, 3H), 7.38 (d, J=6.10 Hz, 1H), 7.64 (d, J=6.10
Hz, 1H), 8.63 (d, J=2.03 Hz, 1H), 9.14 (d, J=2.03 Hz, 1H); MS
(DCI/NH.sub.3) m/z 178 (M+1).sup.+, 195 (M+NH.sub.4).sup.+.
Example 16B
1-(Thieno[2,3-b]pyridin-5-yl)ethanone oxime
[0238] The product of Example 16A (3.89 g, 22 mmol) was treated
with NH.sub.2OH.H.sub.2O (Aldrich, 1.35 g, 26.4 mmol) in pyridine
(30 mL) and EtOH (30 mL) at 80.degree. for 3 h. It was cooled down
to ambient temperature and concentrated under reduced pressure. The
residue was recrystallized with EtOH (Aldrich, 90%) to give the
title compound (3.86 g, yield, 91.4%) .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 2.37 (s, 3H), 7.30 (d, J=5.76 Hz, 1H), 7.56
(d, J=5.76 Hz, 1H), 7.70 [s(broad.), 1H], 8.28 (d, J=2.03 Hz, 1H),
8.90 (d, J=2.37 Hz, 1H); MS (DCI/NH.sub.3) m/z 193 (M+1).sup.+, 210
(M+NH.sub.4).sup.+.
Example 16C
N-(Thieno[2,3-b]pyridin-5-yl)acetamide
[0239] The product of Example 16B (3.84 g, 20 mmol) was treated
with PCl.sub.5 (Aldrich, 6.26 g, 30 mmol) in benzene (Aldrich,
anhydrous, 100 mL) at 80.degree. for 1 h. It was then cooled down
to ambient temperature and poured into ice (100 g). After being
basified with NaOH (Aldrich, 50%) till pH=9-10, the reaction
mixture was extracted with EtOAc (3.times.200 mL). The combined
extracts were washed with brine (2.times.50 mL) and concentrated.
The residue was purified with chromatography (SiO.sub.2,
EtOAc/hexane, v. 50/50, R.sub.f=0.40) to give the title compound
(2.10 g, yield, 54.7%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
ppm 2.26 (s, 3H), 7.24 (s, 1H), 7.56 (d, J=6.10 Hz, 1H), 8.45 (d,
J=2.03 Hz, 1H), 8.69 (d, J=2.03 Hz, 1H); MS (DCI/NH.sub.3) m/z 193
(M+1).sup.+.
Example 16D
Thieno[2,3-b]pyridin-5-amine
[0240] The product of Example 16C (1.92 g, 10 mmol) was treated
with concentrated HCl (Aldrich, 30 mL) at 800.degree. for 14 h. It
was then cooled down to ambient temperature and the pH adjusted
with NaOH (Aldrich, 50%) base until pH=8-9. The reaction mixture
was extracted with CHCl.sub.3 (3.times.100 mL). The combined
extracts were washed with brine (2.times.30 mL) and concentrated to
give the title compound (1.38 g, yield, 92.0%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. ppm 7.13 (d, J=5.76 Hz, 1H), 7.47 (d,
J=2.71 Hz, 1H), 7.56 (d, J=5.76 Hz, 1H), 8.07 (d, J=2.37 Hz, 1H);
MS (DCI/NH.sub.3) m/z 151 (M+1).sup.+.
Example 16E
5-Bromothieno[2,3-b]pyridine
[0241] The product of Example 16D (1.35 g, 9.0 mmol) was treated
with iso-amylnitrite (Aldrich, 2.10 g, 18.0 mmol) and CuBr.sub.2
(Aldrich, 4.03 g, 18.0 mmol) in MeCN (20 mL) at ambient temperature
overnight. The reaction mixture was quenched with saturated
NH.sub.4Cl (20 mL) and then extracted with EtOAc (3.times.50 mL).
The combined extracts were washed with brine (2.times.30 mL) and
concentrated. The residue was purified with chromatography
(SiO.sub.2, EtOAc/hexane, v. 80120. R.sub.f=0.80) to give the title
compound (1.03 g, yield, 53.0%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. ppm 7.22 (d, J=6.10 Hz, 1H), 7.58 (d, J=6.10 Hz, 1H), 8.21
(d, J=2.37 Hz, 1H), 8.61 (d, J=2.03 Hz, 1H): MS (DCI/NH.sub.3) m/z
214 (M+1).sup.+, 216 (M+1).sup.+.
Example 16F
5-(4,4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-b]pyridine
[0242] The title compound was prepared from the product or Example
16E (1.00 g, 7.4 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(Aldrich, 1.43 g, 5.64 mmol) according to the procedure of Example
15A (1.22 g, yield, 99%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
ppm 1.39 (s, 12H), 7.42 (d, J=6.10 Hz, 1H), 7.72 (d, J=5.76 Hz,
1H), 8.55 (d, J=1.36 Hz, 1H), 8.76 (d, J=1.70 Hz, 1H); MS
(DCI/NH.sub.3) m/z 261 (M+1).sup.+.
Example 16G
3H-(4'r)-1'-Azaspiro[5-(thieno[2,3-b]pyridin-5-yl)-benzofuran-2,4']-tricyc-
lo[3.3.1.1.sup.3,7]decane
[0243] The title compound was prepared from the product of Example
7A (160 mg 0.50 mmol) and Example 16F (196 mg, 0.75 mmol) according
to the procedure of Example 3A (80 mg, yield, 42.7%). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. ppm 1.65-1.80 (m, 1H), 1.83-1.92 (m,
2H), 2.00-2.26 (m, 4H), 3.00-3.19 (m, 4H), 3.34 (s, 2H), 3.63 (d,
J=12.88 Hz, 2H), 6.89 (d, J=8.48 Hz, 1H), 7.41 (d, J=6.10 Hz, 1H),
7.46 (dd, J=8.48, 2.03 Hz, 1H), 7.55 (d, J=1.70 Hz, 1H), 7.74 (d,
J=5.76 Hz, 1H), 8.38 (d, J=2.03 Hz, 1H), 8.71 (d, J=2.37 Hz, 1H):
MS (DCI/NH.sub.3) m/z=375 (M+H).sup.+.
Compositions of the Invention
[0244] 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.
[0245] The term "pharmaceutically acceptable carrier," as used
herein, means a non-toxic, 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; 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 non-toxic 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.
[0246] 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.
[0247] 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.
[0248] 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.
[0249] 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, a
parenterally administered drug form can be administered by
dissolving or suspending the drug in an oil vehicle.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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 in addition to, or alternatively with only, 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; c) 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.
[0256] 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.
[0257] 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.
[0258] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating 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.
[0259] 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.
[0260] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0261] 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.
[0262] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal fats,
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0263] 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.
[0264] 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 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.
[0265] 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.
[0266] 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.
[0267] 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 benefit/risk ratio, and are
effective for their intended
[0268] 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.
[0269] Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate (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.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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).
[0276] The invention also contemplates pharmaceutically acceptable
compounds that when administered to a patient in need may be
converted through in vivo biotransformation into compounds of
formula (I).
Determination of Biological Activity
[0277] 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]-methyllycaconitine (MLA) binding assay, or the
[.sup.3H]-DPPB binding assay, and considering the
[.sup.3H]-cytisine binding assay, which were performed as described
below.
[.sup.3H]-Cytisine Binding
[0278] 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 NaCl/5 mM KCl/2 mM CaCl.sub.2/2 mM MgCl.sub.2/50 mM
Tris-Cl, pH 7.4, 4.degree. C.). Samples containing 100-200 .mu.g of
protein and 0.75 nM [.sup.3H]-cytisine (30 C.sub.i/mmol; Perkin
Elmer/NEN 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/5 mM KCl/2 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.1 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]-Methyllyeaconitine (MLA) Binding
[0279] Binding conditions were similar to those for
[.sup.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 [.sup.3H]-MLA (25
C.sub.i/mmol; Perkin Elmer/NEN Life Science Products. Boston. MA)
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. Non-specific 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 .mu.L)
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
[0280] [.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 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]-DPPB 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-bi-
cyclo[2.2.1]heptane; iodide Preparation
[0281]
[Methyl-.sup.3H]2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-az-
onia-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
[0282] 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 was 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/NH.sub.3) m/z
353 (M+H).sup.+.
Step 2: Preparation of (S,S)-2-Methyl
5-(6-phenyl-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane
[0283] 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, 1.0 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
CH.sub.2Cl.sub.2--CH.sub.3OH--NH.sub.4OH (95:5:1) to provide the
title compound as an off-white solid (2.50 g, 96%): MS
(DCI/NH.sub.3) m/z 267 (M+H).sup.+.
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)
[0284] [.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 .mu.mole 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)
[0285] About 7 mCi of [.sup.3H]-DPPB 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.
[.sup.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 [.sup.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
[0286] [.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 .mu.L 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 C18(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.
[0287] 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]-Cytisine binding values of compounds of the invention
ranged from about 50 nanomolar to at least 100 micromolar.
Preferred compounds typically exhibited greater potency at .alpha.7
receptors compared to .alpha.4.beta.2 receptors. The determination
of preferred compounds typically considered the K.sub.i value as
measured by MLA assay in view of the K.sub.i value as measured by
[.sup.3H]-cytisine binding, such that in the formula
D=K.sub.i.sup.3.sub.H-cytisine/K.sub.i MLA. D is greater than about
50. Alternatively, the K.sub.i value as measured by [.sup.3H]-DPPB
assay can be used in place of the K.sub.i MLA such that in the
formula D'=K.sub.i.sup.3.sub.H-cytisine/K.sub.i[3H]-DITB. D' is
greater than about 50.
[0288] Compounds of the invention are .alpha.7 nAChRs ligands that
modulate function of 0.7 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.
Methods of the Invention
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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
.beta.-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.
[0293] 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
post-mortem 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.
[0294] 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.
[0295] 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.
[0296] 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.
[0297] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting
cognition, neurodegeneration, and schizophrenia.
[0298] 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,
(Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 2002). 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.
[0299] 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.
[0300] 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.
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. 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.
[0301] 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. 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.
[0302] Compounds of the invention are .alpha.7 nAChRs ligands that
modulate function of 0.7 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.
[0303] 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.
[0304] 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.
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 and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
* * * * *