U.S. patent application number 11/517064 was filed with the patent office on 2008-09-25 for amino-aza-adamantane derivatives and methods of use.
This patent application is currently assigned to Abbott Laboratories. Invention is credited to David Anderson, William Bunnelle, Diana Nersesian, Michael Schrimpf, Kevin Sippy.
Application Number | 20080234308 11/517064 |
Document ID | / |
Family ID | 37894920 |
Filed Date | 2008-09-25 |
United States Patent
Application |
20080234308 |
Kind Code |
A2 |
Schrimpf; Michael ; et
al. |
September 25, 2008 |
Amino-Aza-Adamantane Derivatives and Methods of Use
Abstract
The invention relates to amine-substituted aza-adamantane
derivatives, compositions comprising such compounds, and methods of
treating conditions and disorders using such compounds and
compositions. Radiolabelled compounds useful for evaluating the
binding affinity to .alpha.7 nicotinic acetylcholine receptors also
are described.
Inventors: |
Schrimpf; Michael;
(Grayslake, IL) ; Sippy; Kevin; (Antioch, IL)
; Anderson; David; (Lake Bluff, IL) ; Bunnelle;
William; (Mundelein, IL) ; Nersesian; Diana;
(Gurnee, IL) |
Correspondence
Address: |
PAUL D. YASGER;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
UNITED STATES
847-935-3325
847-938-2623
Patents_Abbott_Park@abbott.com
|
Assignee: |
Abbott Laboratories
Building AP6A-1, Department 0377 100 Abbott Park Road
Abbott Park
IL
60064-6008
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20070072892 A1 |
March 29, 2007 |
|
|
Family ID: |
37894920 |
Appl. No.: |
11/517064 |
Filed: |
September 7, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60/720,326 |
Sep 23, 2005 |
|
|
|
Current U.S.
Class: |
514/291 ;
546/97 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 9/10 20180101; A61P 25/18 20180101; A61P 25/28 20180101; A61P
15/08 20180101; A61P 15/04 20180101; A61P 17/02 20180101; A61P
25/14 20180101; A61P 25/00 20180101; A61P 9/00 20180101; A61P 25/04
20180101; A61P 21/02 20180101; A61P 43/00 20180101; C07D 487/04
20130101 |
Class at
Publication: |
514/291 ;
546/097 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; C07D 221/22 20060101 C07D221/22 |
Claims
1. A compound of formula (I) ##STR13## or a pharmaceutically
acceptable salt or prodrug thereof, wherein X.sub.1 is a bond or is
selected from the group consisting of --O--, --O-alkylene,
--NR.sub.2-- and --NR.sub.2-alkylene, wherein the oxygen atom of
O-alkylene and the nitrogen atom of --NR.sub.2-alkylene is attached
to the parent molecular moiety; A is selected from the group
consisting of --Ar.sub.1, --Ar.sub.2--Y--Ar.sub.3 and --Ar.sub.4;
Ar.sup.1 is aryl, provided that if Ar.sup.1 is a phenyl ring
containing a meta substituted halogen group, then the phenyl can
not be substituted with both methoxy and --NH.sub.2; Ar.sub.2 is
selected from the group consisting of aryl and heteroaryl; Ar.sub.3
is selected from the group consisting of aryl and heteroaryl;
Ar.sub.4 is selected from the group consisting of heteroaryl and
heterocycle, provided that Ar.sub.4 is not benzimidazolyl,
2,3-dihydro-1H-indolyl or imidazole[1,2-a]pyridine; Y is a bond or
is selected from the group consisting of --O--, --S-- and
--NR.sub.3--; and R.sub.1, R.sub.2 and R.sub.3 are individually
selected from the group consisting of hydrogen and C.sub.1-C.sub.6
alkyl; with the provision that the compound is not selected from
the group consisting of
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-benzamide;
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-3,5-dichloro-benzamide;
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-2-methoxy-benzamide;
1-H-indole-3-carboxylic
acid(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
(4.alpha.,.beta.)-4-amino-N-[1-azaadamantan-4-yl]-5-chloro-2-methoxy
benzamide; 6-chloro-imidazo[1,2-a}pyridine-8-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)amide; and
3-ethyl-indolizine-1-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
2. The compound according to claim 1, wherein X.sub.1 is a bond; A
is Ar.sub.1; Ar.sub.1 is aryl, wherein the phenyl is substituted
with 1, 2, 3, 4 or 5 substituents independently selected from the
group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2
and (NZ.sub.3Z.sub.4)carbonyl, and wherein the naphthyl is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl, provided that if Ar.sup.1 is a phenyl
ring containing a meta substituted halogen group, then the phenyl
can not be substituted with both methoxy and --NH.sub.2; 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 or Z.sub.1 and
Z.sub.2 together with the nitrogen atom to which they are attached
form a heterocyclic ring; Z.sub.3 and Z.sub.4 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and arylalkyl; and Z.sub.5 and Z.sub.6 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and arylalkyl; with the provision that the compound is
not selected from the group consisting of
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-benzamide;
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-benzamide;
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-3,5-dichloro-benzamide;
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-2-methoxy-benzamide;
and
(4.alpha.,.beta.)-4-amino-N-[1-azaadamantan-4-yl]-5-chloro-2-methoxy
benzamide.
3. The compound according to claim 1, wherein X.sub.1 is a bond; A
is Ar.sub.1; and Ar.sub.1 is selected from the group consisting of
3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl,
2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl,
3-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 4-methoxyphenyl,
3-methoxyphenyl, 2-ethoxyphenyl, 3-trifluoromethoxyphenyl,
1-naphthyl, 2-naphthyl and 1-hydroxy-2-naphthyl.
4. The compound according to claim 1, wherein X.sub.1 is a bond; A
is --Ar.sub.2--Y--Ar.sub.3; Ar.sub.2 is selected from the group
consisting of phenyl, a 5 or 6 membered monocyclic heteroaryl ring
and a bicyclic heteroaryl ring, wherein Ar.sub.2 is substituted or
unsubstituted wherein each substituent is independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
--NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; Ar.sub.3 is
selected from the group consisting of phenyl, a 5 or 6 membered
monocyclic heteroaryl ring and a bicyclic heteroaryl ring, wherein
Ar.sup.3 is substituted or unsubstituted wherein each substituent
is independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2 together with the
nitrogen atom to which they are attached form a heterocyclic ring;
Z.sub.3 and Z.sub.4 are each independently selected from the group
consisting of hydrogen, alkyl, aryl and arylalkyl; Z.sub.5 and
Z.sub.6 are each independently selected from the group consisting
of hydrogen, alkyl, aryl and arylalkyl; and Y is a bond or is
--O--.
5. The compound according to claim 1, wherein Ar.sub.2 is phenyl
and monocyclic X.sub.1 is a bond; A is --Ar.sub.2--Y--Ar.sub.3;
Ar.sub.2 is selected from the group consisting of phenyl and a 5 or
6 membered monocyclic heteroaryl ring, wherein Ar.sub.2 is
substituted or unsubstituted wherein each substituent is
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl; Ar.sub.3 is selected from the group
consisting of phenyl, a 5 or 6 membered monocyclic heteroaryl ring
and a bicyclic heteroaryl ring, wherein Ar.sub.3 is substituted or
unsubstituted wherein each substituent is independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
--NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2
together with the nitrogen atom to which they are attached form a
heterocyclic ring; Z.sub.3 and Z.sub.4 are each independently
selected from the group consisting of hydrogen, alkyl, aryl and
arylalkyl; Z.sub.5 and Z.sub.6 are each independently selected from
the group consisting of hydrogen, alkyl, aryl and arylalkyl; and Y
is a bond or is --O--.
6. The compound according to claim 1, wherein Ar.sup.2 is phenyl
X.sub.1 is a bond; A is --Ar.sub.2--Y--Ar.sub.3; Ar.sub.2 is phenyl
which is optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl; Ar.sub.3 is selected from the group
consisting of phenyl, a 5 or 6 membered monocyclic heteroaryl ring
and a bicyclic heteroaryl ring, wherein Ar.sub.3 is substituted or
unsubstituted wherein each substituent is independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
--NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2
together with the nitrogen atom to which they are attached form a
heterocyclic ring; Z.sub.3 and Z.sub.4 are each independently
selected from the group consisting of hydrogen, alkyl, aryl and
arylalkyl; Z.sub.5 and Z.sub.6 are each independently selected from
the group consisting of hydrogen, alkyl, aryl and arylalkyl; and Y
is a bond or is --O--.
7. The compound according to claim 1, wherein Ar2 is a monocyclic
heteroaryl X.sub.1 is a bond; A is --Ar.sub.2--Y--Ar.sub.3;
Ar.sub.2 is a 5 or 6 membered monocyclic heteroaryl ring which is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl; Ar.sub.3 is selected from the group
consisting of phenyl, a 5 or 6 membered monocyclic heteroaryl ring
and a bicyclic heteroaryl ring, wherein Ar.sub.3 is substituted or
unsubstituted wherein each substituent is independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
--NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2
together with the nitrogen atom to which they are attached form a
heterocyclic ring; Z.sub.3 and Z.sub.4 are each independently
selected from the group consisting of hydrogen, alkyl, aryl and
arylalkyl; Z.sub.5 and Z.sub.6 are each independently selected from
the group consisting of hydrogen, alkyl, aryl and arylalkyl; and Y
is a bond or is --O--.
8. The compound according to claim 1, wherein Ar.sub.2 is a
bicyclic heteroaryl X.sub.1 is a bond; A is --Ar.sub.2-Y--Ar.sub.3;
Ar.sub.2 is a bicyclic heteroaryl ring which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from the group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
alkyl, alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano,
cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
nitro, --NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; Ar.sub.3 is
selected from the group consisting of phenyl, a 5 or 6 membered
monocyclic heteroaryl ring and a bicyclic heteroaryl ring, wherein
Ar.sub.3 is substituted or unsubstituted wherein each substituent
is independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2 together with the
nitrogen atom to which they are attached form a heterocyclic ring;
Z.sub.3 and Z.sub.4 are each independently selected from the group
consisting of hydrogen, alkyl, aryl and arylalkyl; Z.sub.5 and
Z.sub.6 are each independently selected from the group consisting
of hydrogen, alkyl, aryl and arylalkyl; and Y is a bond or is
--O--.
9. The compound according to claim 1, wherein X.sub.1 is a bond; A
is --Ar4; Ar.sub.4 is selected from the group consisting of a 5 or
6 membered heteroaryl ring, a bicyclic heteroaryl ring and a
heterocycle, wherein Ar.sub.4 is substituted or unsubstituted
wherein each substituent is independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2
and (NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2 together with the
nitrogen atom to which they are attached form a heterocyclic ring;
Z.sub.3 and Z.sub.4 are each independently selected from the group
consisting of hydrogen, alkyl, aryl and arylalkyl; and Z.sub.5 and
Z.sub.6 are each independently selected from the group consisting
of hydrogen, alkyl, aryl and arylalkyl.
10. The compound according to claim 1, wherein X.sub.1 is a bond; A
is --Ar.sub.4; and Ar.sub.4 is selected from the group consisting
of benzofuranyl, benzoxadiazolyl, benzoisoxazole, benzoisothiazole,
benzooxazole, 1,3-benzothiazolyl, benzodioxolyl, benzothiophenyl,
chromenyl, cinnolinyl, furyl, furopyridine, imidazolyl, indolyl,
indazolyl, isoindolyl, isoquinolinyl, isobenzofuran, isoxazolyl,
isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl,
oxazolopyridine, pyrazolyl, pyrrolyl, pyridazinyl, pyradinyl,
pyrazinyl, pyrimadinyl, quinoxalinyl, quinolinyl, thiazolyl,
thienyl, thienopyridine, thiadiazolyl, triazolyl, triazinyl and
thienopyridinyl, wherein Ar.sup.4 is substituted or unsubstituted
wherein each substituent is independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2
and (NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2 together with the
nitrogen atom to which they are attached form a heterocyclic ring;
Z.sub.3 and Z.sub.4 are each independently selected from the group
consisting of hydrogen, alkyl, aryl and arylalkyl; and Z.sub.5 and
Z.sub.6 are each independently selected from the group consisting
of hydrogen, alkyl, aryl and arylalkyl.
11. The compound according to claim 1, wherein X.sub.1 is a bond; A
is --Ar.sub.4; and Ar.sub.4 is selected from the group consisting
of 6-(1,3-benzothiazolyl), 5-benzodioxolyl, 2-benzothiophenyl,
3-benzothiophenyl, 5-benzothiophenyl, 3-chromenyl, 5-indolyl,
6-indolyl, 5-thieno[2,3-c]pyridinyl and 6-thieno[3,2-c]pyridinyl,
wherein Ar4 is substituted or unsubstituted wherein each
substituent is independently selected from the group consisting of
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl; 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 or Z.sub.1 and Z.sub.2 together with the
nitrogen atom to which they are attached form a heterocyclic ring;
Z.sub.3 and Z.sub.4 are each independently selected from the group
consisting of hydrogen, alkyl, aryl and arylalkyl; and Z.sub.5 and
Z.sub.6 are each independently selected from the group consisting
of hydrogen, alkyl, aryl and arylalkyl.
12. The compound according to claim 1, wherein X.sub.1 is a bond; A
is --Ar.sub.4; and Ar.sub.4 is ##STR14## X.sub.2 is selected from
the group consisting of --O--, --NR.sub.b-- and --S--; one of
X.sub.4, X.sub.5, X.sub.6 and X.sub.7 may be nitrogen and the
others are CR.sub.a; each occurance of R.sub.a is independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
alkyl, alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano,
cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
nitro, --NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; R.sub.b is
selected from the group consisting of hydrogen and alkyl; 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 or Z.sub.1 and
Z.sub.2 together with the nitrogen atom to which they are attached
form a heterocyclic ring; Z.sub.3 and Z.sub.4 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and arylalkyl; and Z.sub.5 and Z.sub.6 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and arylalkyl.
13. The compound selected from the group consisting of
benzo[b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[b]thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[b]thiophene-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[b]thiophene-3-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[b]thiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[b]thiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
1H-indole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
1H-indole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
1H-indole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
1H-indole-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
thieno[2,3-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
thieno[2,3-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
thieno[3,2-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
thieno[3,2-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzothiazole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzothiazole-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2-methyl-1H-benzoimidazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2-methyl-1H-benzoimidazole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2-aminobenzothiazole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-chlorothiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-chlorothiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
4-phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
4-phenylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-phenylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(pyridin-2-yl)-thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(pyridin-2-yl)-thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2,2'-bithiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2,2'-bithiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(3-trifluoromethylphenyl)-furan-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(3-trifluoromethylphenyl)-furan-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(2-nitrophenyl)-furan-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.37]dec-4-yl)-amide;
5-(2-nitrophenyl)-furan-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2-(pyridin-4-yl)-thiazole-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.37]dec-4-yl)-amide;
2-(pyridin-4-yl)-thiazole-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2-(thiophen-2-yl)-thiazole-4-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(thiophen-2-yl)-1H-pyrazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
N-[(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-(thiophen-2-yl)-benzami-
de;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-(thiophen-2-yl)-ben-
zamide;
N-[(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3,4-dichlorobenza-
mide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3,4-dichlorobenzami-
de;
N-[(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-chlorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.37]dec-4-yl]-4-chlorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-chlorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2,3-dichlorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2,4-dichlorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-fluorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-fluorobenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-hydroxybenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-hydroxybenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-methoxybenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-methoxybenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2-ethoxybenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-trifluoromethoxybenzami-
de;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-phenoxybenzamide;
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-methylsulfanylbenzamide-
; thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-methylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
3-methylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
naphthalene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
1-hydroxynaphthalene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
naphthalene-1-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
6-chloro-2H-chromene-3-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[1,3]dioxole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2,3-dihydrobenzo[1,4]dioxine-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
2,3-dihydrobenzo[1,4]dioxine-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
3-methyl-benzofuran-2-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; 2-naphthoic acid
(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzofuran-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[d][1,2,3]thiadiazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
isoquinoline-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
benzo[c][1,2,5]thiadiazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-(2-methylthiazol-4-yl)thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
3-thiophen-2-yl)benzoic acid
(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
thieno[3,2-b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
thieno[2,3-b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
5-chlorobenzofuran-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide;
1H-indazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; and
1H-indazole-4-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
14. The method of selectively modulating the effects of .alpha.7
nicotinic acetylcholine receptors in a mammal comprising
administering an effective amount of a compound of formula (II)
##STR15## or a pharmaceutically suitable salt or prodrug thereof,
wherein X.sub.1 is a bond or is selected from the group consisting
of --O--, --O-alkylene, --NR.sub.2-- and --NR.sub.2-alkylene; A is
selected from the group consisting of Ar.sup.1,
--Ar.sub.2-Y--Ar.sub.3 and Ar.sub.4; Ar.sup.1 is aryl; Ar.sub.2 is
selected from the group consisting of aryl and heteroaryl; Ar.sub.3
is selected from the group consisting of aryl and heteroaryl;
Ar.sub.4 is selected from the group consisting of heteroaryl and
heterocycle; Y is a bond or is selected from the group consisting
of --O--, --S-- and --NR.sub.3--; and R.sub.1, R.sub.2 and R.sub.3
are individually selected from the group consisting of hydrogen and
C.sub.1-C.sub.6 alkyl.
15. The method according to claim 14, wherein the condition or
disorder or deficit is selected from the group consisting of a
memory disorder, cognitive disorder, neurodegeneration, and
neurodevelopmental disorder.
16. The method according to claim 14, wherein the condition or
disorder is selected from the group consisting of 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, schizoaffective disorder, bipolar
and manic disorders, diminished CNS function associated with
traumatic brain injury, acute pain, post-surgical pain, chronic
pain, inflammatory pain and other neuroimmunomodulatory
diseases.
17. The method according to claim 14, wherein the condition or
disorder is cognitive deficits associated with schizophrenia,
Alzheimer's disease, mild cognitive impairment and age-associated
memory impairment.
18. The method according to claim 14, further comprising
administering a compound of formula (II) in combination with an
atypical antipsychotic.
19. The method according to claim 14, wherein the condition,
disorder or disease progression can be improved by altering disease
modifying processes implicated in neurodegenerative diseases.
20. The method according to claim 14, wherein the condition or
disorder is selected from the group consisting of 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, wound
healing, and other complications associated with diabetes.
21. A compound of formula (III): ##STR16## wherein: m, n, and q
each are independently 0, 1, or 2; 1 and p each are independently 1
or 2; the sum of l, m, n, p, and q is 3, 4, 5, or 6; A is selected
from: ##STR17## B is selected from substituted or unsubstituted
phenyl; and at least one of the available atoms within a compound
of formula (III) is replaced with a radioisotope.
22. A compound according to claim 21, wherein the compound of
formula (III) is:
[.sup.3H]-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane, iodide (DPPB);
[.sup.3H]-(R,R)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane, iodide;
[.sup.3H]-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4--
c]pyrrol-2-ium, iodide;
[.sup.3H]-(1R,6S)-9,9-dimethyl-3-(6-phenyl-pyridazin-3-yl)-3-aza-9-azonia-
-bicyclo[4.2.1]nonane, iodide; and
[.sup.3H]-(1S,6R)-9,9-dimethyl-3-(6-phenyl-pyridazin-3-yl)-3-aza-9-azonia-
-bicyclo[4.2.1]nonane, iodide.
23. Use of a radiolabelled form of a compound of formula (III) for
determining binding affinity to .alpha.7 nicotinic acetylcholine
receptors.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Technical Field
[0002] The invention relates to amine-substituted aza-adamantane
derivatives, compositions comprising such compounds, and methods of
treating conditions and disorders using such compounds and
compositions.
[0003] 2. Description of Related Technology
[0004] Nicotinic acetylcholine receptors (nAChRs) are widely
distributed throughout the central (CNS) and peripheral (PNS)
nervous systems. Such receptors play an important role in
regulating CNS function, particularly by modulating release of a
wide range of neurotransmitters, including, but not necessarily
limited to acetylcholine, norepinephrine, dopamine, serotonin and
GABA. Consequently, nicotinic receptors mediate a very wide range
of physiological effects, and have been targeted for therapeutic
treatment of disorders relating to cognitive function, learning and
memory, neurodegeneration, pain and inflammation, psychosis and
sensory gating, mood and emotion, among others.
[0005] 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.
[0006] 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.
[0007] The .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). For example, .alpha.7 nAChRs have been linked to
conditions and disorders related to attention deficit disorder,
attention deficit hyperactivity disorder (ADHD), Alzheimer's
disease (AD), mild cognitive impairment, senile dementia, dementia
associated with Lewy bodies, dementia associated with Down's
syndrome, AIDS dementia, Pick's Disease, as well as cognitive
deficits associated with schizophrenia, among other systemic
activities.
[0008] The activity at the .alpha.7 nAChRs can be modified or
regulated by the administration of .alpha.7 nAChR ligands. The
ligands can exhibit antagonist, agonist, or partial agonist
properties. Thus, .alpha.7 ligands have potential in treatment of
various cognitive disorders.
[0009] Although compounds demonstrating activity at the .alpha.7
nAChRs are known, it would be beneficial to provide compounds that
interact selectively with .alpha.7-containing neuronal nAChRs
compared to other subtypes.
SUMMARY OF THE INVENTION
[0010] The invention is directed to amino-aza-adamantane containing
compounds as well as compositions comprising such compounds, and
method of using the same.
[0011] One aspect of the present invention is directed toward a
compound of formula (I) ##STR1## or a pharmaceutically suitable
salt or prodrug thereof, wherein
[0012] X.sub.1 is a bond or is selected from --O--, --O-alkyl,
--NR.sup.2-- and --NR.sup.2-alkyl, wherein the oxygen atom of
--O-alkyl and the nitrogen atom of --NR.sup.2-alkyl is attached to
the parent molecular moiety;
[0013] A is selected from Ar.sup.1, --Ar.sup.2--Y--Ar.sup.3 and
Ar.sup.4;
[0014] Ar.sup.1 is aryl, provided that if Ar.sup.1 is a phenyl ring
containing a meta-substituted halogen group, then the phenyl can
not be substituted with both methoxy and --NH.sub.2;
[0015] Ar.sup.2 is selected from the aryl and heteroaryl;
[0016] Ar.sup.3 is selected from aryl and heteroaryl;
[0017] Ar.sup.4 is selected from heteroaryl and heterocycle,
provided that Ar.sup.4 is not benzimidazolyl,
2,3-dihydro-1H-indolyl or imidazole[1,2-a]pyridine;
[0018] Y is a bond or is selected from --O--, --S-- and
--NR.sup.3--; and
[0019] R.sup.1, R.sup.2 and R.sup.3 are individually selected from
hydrogen and C.sub.1-C.sub.6 alkyl;
[0020] with the provision that the compound is not selected from
the group consisting of [0021]
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-benzamide; [0022]
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-3,5-dichloro-benzamide;
[0023]
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-2-methoxy-benzamide;
[0024] 1-H-indole-3-carboxylic
acid(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0025]
(4.alpha.,.beta.)-4-amino-N-[1-azaadamantan-4-yl]-5-chloro-2-methoxy
benzamide; [0026] 6-chloro-imidazo[1,2-a}pyridine-8-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)amide; and [0027]
3-ethyl-indolizine-1-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
[0028] 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.
[0029] Yet another 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), 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, 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.
[0030] Radiolabelled compounds useful for evaluating the binding
affinity of compounds, for example amine-substituted aza-adamantane
derivatives, to .alpha.7 nicotinic acetylcholine receptors also are
described herein.
[0031] The compounds, compositions comprising the compounds, and
methods for treating or preventing conditions and disorders by
administering the compounds are further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0032] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0033] 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.
[0034] 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--.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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--.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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--.
[0056] 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.
[0057] 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. The
bicyclic aryl is attached to the parent molecular moiety through
any carbon atom contained within the bicyclic aryl. 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. The tricyclic aryl is attached to the parent molecular
moiety through any carbon atom contained within the tricyclic aryl.
Representative examples of tricyclic aryl ring include, but are not
limited to, azulenyl, dihydroanthracenyl, fluorenyl, and
tetrahydrophenanthrenyl.
[0058] 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.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] The term "azido" as used herein, means a --N.sub.3
group.
[0069] The term "carbonyl" as used herein, means a --C(O)--
group.
[0070] The term "carboxy" as used herein, means a --CO.sub.2H
group.
[0071] 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.
[0072] The term "cyano" as used herein, means a --CN group.
[0073] 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.
[0074] 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.
[0075] 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 non-adjacent carbon atoms of
the monocyclic ring are linked by an alkylene bridge of between one
and three additional carbon atoms. Representative examples of
bicyclic ring systems include, but are not limited to,
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and
bicyclo[4.2.1]nonane. 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[3.3.1.1.sup.3,7]nonane and tricyclo[3.3.1.1.sup.3,7]decane
(adamantane).
[0076] The cycloalkyl groups of the present 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.
[0077] 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] The term "formyl" as used herein, means a --C(O)H group.
[0083] 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.
[0084] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0085] 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.
[0086] 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.
[0087] The term "heteroaryl," as used herein, means a monocyclic
heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a
5 or 6 membered ring. The 5 membered ring contains two double bonds
and one, two, three or four nitrogen atoms and optionally one
oxygen or sulfur atom. The 6 membered ring contains three double
bonds and one, two, three or four nitrogen atoms. 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, benzofuranyl, benzoxadiazolyl, benzoisoxazole,
benzoisothiazole, benzooxazole, 1,3-benzothiazolyl,
benzothiophenyl, cinnolinyl, furopyridine, indolyl, indazolyl,
isobenzofuran, isoindolyl, isoquinolinyl, naphthyridinyl,
oxazolopyridine, quinolinyl, quinoxalinyl and thienopyridinyl,
[0088] The heteroaryl groups of the present 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 present
invention that are substituted may be present as tautomers. The
present invention encompasses all tautomers including non-aromatic
tautomers.
[0089] 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.
[0090] 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 beteroarylalkyl 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] 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.
[0098] 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, oxadiazolidinyl, 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.
[0099] 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.
[0100] 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.
[0101] 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, 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.
[0102] The term "heterocyclealkylthio" 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-ylethylthio, 3-quinolin-3-ylpropythio, and
5-pyridin-4-ylpentylthio.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] The term "hydroxy" as used herein, means an --OH group.
[0110] 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.
[0111] 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).
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] The term "mercapto" as used herein, means a --SH group.
[0120] 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.
[0121] 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.
[0122] 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).
[0123] The term "nitro" as used herein, means a --NO.sub.2
group.
[0124] 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 present
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.
[0125] 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.
[0126] 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.
[0127] 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 of (NZ.sub.3Z.sub.4)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0128] The term "(NZ.sub.3Z.sub.4)sulfonyl" as used herein, means a
NZ.sub.3Z.sub.4 group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NZ.sub.3Z.sub.4)sulfonyl include, but
are not limited to, aminosulfonyl, (methylamino)sulfonyl,
(dimethylamino)sulfonyl, and (ethylmethylamino)sulfonyl.
[0129] The term "oxo" as used herein, means a .dbd.O moiety.
[0130] The term "sulfinyl" as used herein, means a --S(O)--
group.
[0131] The term "sulfonyl" as used herein, means a --SO.sub.2--
group.
[0132] 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.
[0133] 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
[0134] Compounds of the invention can have the formula (I) as
described in the Summary of the Invention.
[0135] In compounds of formula (I), R.sup.1 is selected from
hydrogen and C.sub.1-C.sub.6 alkyl. Preferably, R.sup.1 is
hydrogen.
[0136] X.sub.1 is a bond or is selected from --O--, --O-alkyl,
--NR.sup.2-- and --N-alkyl, wherein R.sup.2 is selected from
hydrogen and C.sub.1-C.sub.6 alkyl. The oxygen atom of --O-alkyl
and the nitrogen atom of --NR.sup.2-alkyl each respectively is
attached to the parent molecular moiety. A preferred group for
X.sub.1 is wherein X.sub.1 is a bond.
[0137] The group represented by A can be a group represented by
Ar.sup.1, --Ar.sup.2--Y--Ar.sup.3 or Ar.sup.4.
[0138] In one embodiment, A represents Ar.sup.1. Ar.sup.1 is aryl,
particularly naphthyl or phenyl. If X.sub.1 is a bond and Ar.sup.1
is a phenyl ring containing a meta-substituted halogen group, for
example chloro, fluoro, or iodo, then the phenyl group can not also
be substituted with both a methoxy substitutent and a --NH.sub.2
substituent in addition to the halogen group. Suitable groups for
Ar.sup.1 are, for example, phenyl, particularly phenyl groups
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
--NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl; provided that the
group is not phenyl, 3,5-dichlorophenyl, or 2-methoxy. More
preferred phenyl groups for Ar.sup.1 are, for example,
3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl,
2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl,
3-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 4-methoxyphenyl,
3-methoxyphenyl, 2-ethoxyphenyl, and 3-trifluoromethoxyphenyl.
[0139] Other suitable groups for Ar.sup.1 are, for example,
naphthyl, particularly naphthyl groups wherein the naphthyl group
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
--NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl. More preferred
naphthyl for Ar.sup.1 groups are, for example, 1-naphthyl,
2-naphthyl and 1-hydroxy-2-naphthyl.
[0140] When Ar.sup.1 is aryl, it is preferred that X.sub.1 is a
bond.
[0141] In another embodiment, A is a group represented by
Ar.sup.2--Y--Ar.sup.3, wherein Ar.sup.2 is aryl or heteroaryl; Y is
a bond, --O--, --S-- and --NR.sup.3; and Ar.sup.3 is aryl or
heteroaryl, and also wherein Ar.sup.2, Y and Ar.sup.3 are selected
independently of each other. Preferably, Ar.sup.2 phenyl and a 5 or
6 membered monocyclic heteroaryl ring. Ar.sup.2 can be
unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents
selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2
and (NZ.sub.3Z.sub.4)carbonyl, wherein Z.sub.1 and Z.sub.2 are each
independently selected from hydrogen, alkyl, alkylcarbonyl,
alkoxycarbonyl, aryl, arylalkyl, formyl and
(NZ.sub.5Z.sub.6)carbonyl or Z.sub.1 and Z.sub.2 together with the
nitrogen atom to which they are attached form a heterocyclic ring;
and Z.sub.3 and Z.sub.4 are each independently selected from
hydrogen, alkyl, aryl and arylalkyl. Z.sub.5 and Z.sub.6 are each
independently selected from hydrogen, alkyl, aryl and arylalkyl.
Preferred groups for Ar.sup.2 include, but are not limited to,
thienyl, furyl, thiazolyl, pyrazolyl, thienyl and phenyl, each of
which can be further substituted as described for Ar.sup.2.
Preferred substituents attached to Ar.sup.2 include halo and
alkyl.
[0142] Preferrably, Ar.sup.3 is phenyl, a 5 or 6 membered
monocyclic heteroaryl ring, or a bicyclic heteroaryl ring. Ar.sup.3
can be unsubstituted or substituted with 1, 2, 3, or 4 substituents
selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2
and (NZ.sub.3Z.sub.4)carbonyl, wherein Z.sub.1, Z.sub.2, Z.sub.3,
and Z.sub.4 are as described for Ar.sup.2. Preferred groups for
Ar.sup.3 include, but are not limited to, phenyl, pyridine,
thienyl, thiazolyl, trifluoromethylphenyl, and nitrophenyl, each of
which can be further substituted as described for Ar.sup.3.
[0143] When Y is --NR.sup.3--, R.sup.3 is selected from hydrogen
and C.sub.3-C.sub.6 alkyl. It is preferred that Y is a bond or is
--O--. More preferably, Y is a bond. In one embodiment, there is
described compounds wherein A is Ar.sup.2--Y--Ar.sup.3 Ar.sup.2 is
thienyl, furyl, thiazolyl or pyrazolyl, Y is a bond and Ar.sup.3 is
phenyl, pyridinyl or thienyl.
[0144] In another embodiment, A is a group represented by Ar.sup.4.
Ar.sup.4 can be heteroaryl or heterocycle, provided that when
X.sub.1 is a bond Ar.sup.4 is not a group that is benzimidazolyl,
2,3-dihydro-1H-indolyl, imidazole[1,2-a]pyridine or 3-indolyl,
including further substituted forms of such groups. Preferred
Ar.sup.4 groups are selected from a 5 or 6 membered heteroaryl
ring, a bicyclic heteroaryl ring and a heterocycle. Ar.sup.4 can be
unsubstituted or substituted with a substituent selected from
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl, wherein Z.sub.1, Z.sub.2, Z.sub.3, and
Z.sub.4 are as previously defined for Ar.sup.2. Preferred Ar.sup.4
groups include, but are not limited to, benzofuranyl,
benzoxadiazolyl, benzoisoxazole, benzoisothiazole, benzooxazole,
1,3-benzothiazolyl, benzodioxolyl, benzothiophenyl, chromenyl,
cinnolinyl, furyl, furopyridine, imidazolyl, indolyl, indazolyl,
isobenzofuran, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl,
naphthyridinyl, oxadiazolyl, oxazolyl, oxazolopyridine, pyrazolyl,
pyrrolyl, pyridazinyl, pyradinyl, pyrazinyl, pyrimadinyl,
quinoxalinyl, quinolinyl, thiazolyl, thienyl, thienopyridine,
thiadiazolyl, triazolyl, triazinyl and thienopyridinyl, wherein
each group can be further substituted as defined for Ar.sup.4. More
preferred groups for Ar.sup.4 are, for example,
6-(1,3-benzothiazolyl), 5-benzodioxolyl, 2-benzothiophenyl,
3-benzothiophenyl, 5-benzothiophenyl, 3-chromenyl, 5-indolyl,
6-indolyl, furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl,
furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-c]pyridinyl,
thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, and
thieno[3,2-c]pyridinyl.
[0145] Examples of a preferred group include, but are not limited
to, compounds of the formula: ##STR2## wherein X.sub.2 is selected
from --O--, --NR.sub.b-- and --S--, one of X.sub.4, X.sub.5,
X.sub.6 and X.sub.7 may be nitrogen and the others are CR.sub.a,
each occurance of R.sub.a is independently selected from hydrogen,
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, carboxy,
carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, nitro, --NZ.sub.1Z.sub.2 and
(NZ.sub.3Z.sub.4)carbonyl, and R.sub.b is selected from hydrogen
and alkyl.
[0146] It is preferred that X.sub.2 is --S--, such that the
formulas of above represent the groups wherein Ar.sup.4 are:
##STR3## wherein one of X.sub.4, X.sub.5, X.sub.6 and X.sub.7 may
be nitrogen and the others are CR.sub.a, each occurance of R.sub.a
is independently selected from hydrogen, alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
alkyl, alkylcarbonyl, alkylthio, carboxy, carboxyalkyl, cyano,
cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
nitro, --NZ.sub.1Z.sub.2 and (NZ.sub.3Z.sub.4)carbonyl. In one
particular embodiment, X.sub.1 is a bond, and either X.sub.5 or
X.sub.6 is nitrogen.
[0147] In one embodiment, X.sub.1 is a bond, A is Ar.sup.4 and
Ar.sup.4 is 5-furo[2,3-c]pyridinyl, 5-benzothiophen-yl,
2-(5-phenyl)thiophen-yl, 6-1H-indolyl, 5-(2,2'-bithiophen-yl),
6-thieno[3,2-c]pyridinyl, 3-1H-indazolyl or
5-thieno[2,3-c]pyridinyl.
[0148] In another embodiment, X.sub.1 is a bond, A is Ar.sup.4 and
Ar.sup.4 is 5-furo[2,3-c]pyridinyl, 6-1H-indolyl,
6-thieno[3,2-c]pyridinyl or 5-thieno[2,3-c]pyridinyl.
[0149] All suitable compounds, preferred compounds, and example
compounds for Ar.sup.4 can be substituted as described for
Ar.sup.4.
[0150] Suitable groups for X.sub.1, A, Ar.sup.1, Ar.sup.2,
Ar.sup.3, Ar.sup.4, Y, R.sup.1, R.sup.2 and R.sup.3 in compounds of
formula (I) are independently selected. The described embodiments
of the present invention may be combined. Such combination is
contemplated and within the scope of the present invention. For
example, it is contemplated that preferred groups for any of
X.sub.1, A, Ar.sup.1, Ar.sup.2, Ar.sup.3, Ar.sup.4, Y, R.sup.1,
R.sup.2 and R.sup.3 can be combined with groups defined for any
other of X.sub.1, A, Ar.sup.1, Ar.sup.2, Ar.sup.3, Ar.sup.4, Y,
R.sup.1, R.sup.2 and R.sup.3 whether or not such group is
preferred.
[0151] Specific embodiments contemplated as part of the invention
include, but are not limited to compounds of formula (I), or salts
or prodrugs thereof, for example: [0152]
benzo[b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0153]
benzo[b]thiophene-2-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0154]
benzo[b]thiophene-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0155]
benzo[b]thiophene-3-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0156]
benzo[b]thiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0157]
benzo[b]thiophene-5-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0158]
1H-indole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0159]
1H-indole-5-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0160]
1H-indole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0161]
1H-indole-6-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0162]
thieno[2,3-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0163]
thieno[2,3-c]pyridine-5-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0164]
thieno[3,2-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0165]
thieno[3,2-c]pyridine-5-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0166]
benzothiazole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0167]
benzothiazole-6-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0168]
2-methyl-1H-benzoimidazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0169]
2-methyl-1H-benzoimidazole-5-carboxylic acid
(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0170]
2-aminobenzothiazole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.37]dec-4-yl)-amide; [0171]
5-chlorothiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0172]
5-chlorothiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0173]
4-phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0174]
4-phenylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0175]
5-phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0176]
5-phenylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0177]
5-(pyridin-2-yl)-thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0178]
5-(pyridin-2-yl)-thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0179]
2,2'-bithiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0180]
2,2'-bithiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0181]
5-(3-trifluoromethylphenyl)-furan-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0182]
5-(3-trifluoromethylphenyl)-furan-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0183]
5-(2-nitrophenyl)-furan-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0184]
5-(2-nitrophenyl)-furan-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0185]
2-(pyridin-4-yl)-thiazole-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0186]
2-(pyridin-4-yl)-thiazole-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0187]
2-(thiophen-2-yl)-thiazole-4-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0188]
5-(thiophen-2-yl)-1H-pyrazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0189]
N-[(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-(thiophen-2-yl)-benzami-
de; [0190]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-(thiophen-2-yl)-benzami-
de; [0191]
N-[(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3,4-dichlorobenzamide;
[0192]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3,4-dichlorobenza-
mide; [0193]
N-[(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-chlorobenzamide;
[0194]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-chlorobenzamide-
; [0195]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-chlorobenzami-
de; [0196]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2,3-dichlorobenzamide;
[0197]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2,4-dichlorobenza-
mide; [0198]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-fluorobenzamide;
[0199]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-fluorobenzamide-
; [0200]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-hydroxybenzam-
ide; [0201]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-hydroxybenzamide;
[0202]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-methoxybenzamid-
e; [0203]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-methoxybenzamide;
[0204]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2-ethoxybenzamide-
; [0205]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-trifluorometh-
oxybenzamide; [0206]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-phenoxybenzamide;
[0207]
N-[(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-methylsulfanylb-
enzamide; [0208] thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0209]
5-methylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0210]
3-methylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0211]
naphthalene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0212]
1-hydroxynaphthalene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0213]
naphthalene-1-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0214]
6-chloro-2H-chromene-3-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0215]
benzo[1,3]dioxole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0216]
2,3-dihydrobenzo[1,4]dioxine-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0217]
2,3-dihydrobenzo[1,4]dioxine-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0218]
furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0219]
3-methyl-benzofuran-2-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0220]
furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0221] 2-naphthoic
acid (4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0222]
benzofuran-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0223]
benzo[d][1,2,3]thiadiazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0224]
isoquinoline-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0225]
benzo[c][1,2,5]thiadiazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0226]
5-(2-methylthiazol-4-yl)thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0227]
3-thiophen-2-yl)benzoic acid
(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0228]
thieno[3,2-b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0229]
thieno[2,3-b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0230]
5-chlorobenzofuran-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0231]
1H-indazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; and [0232]
1H-indazole-4-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
[0233] 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.
[0234] More particularly, the compounds of the present invention
exist in the forms represented by formula (Ia) and (Ib)
##STR4##
[0235] The isomers (Ia) and (Ib) may be either synthesized
separately by using the individual stereoisomers according to the
Schemes and/or the experimentals described herein. Alternatively,
the individual isomers may be separated by chromatographic methods
from the mixture of both isomers when mixtures of stereoisomers are
used in the synthesis. 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
present invention.
[0236] More specifically, preferred compounds contemplated as part
of the invention include [0237] furo[2,3-c]pyridine-5-carboxylic
acid (1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0238]
furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0239]
benzo[b]thiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0240]
benzo[b]thiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0241]
benzo[b]thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0242]
5-phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0243]
1H-indole-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0244]
2,2'-bithiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0245]
2,2'-bithiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0246]
thieno[3,2-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0247]
thieno[2,3-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0248]
thieno[3,2-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0249]
thieno[2,3-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; and [0250]
1H-indazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
[0251] In addition, other preferred compounds contemplated as part
of the invention include [0252] furo[2,3-c]pyridine-5-carboxylic
acid (1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0253]
1H-Indole-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0254]
thieno[3,2-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; and [0255]
thieno[2,3-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
Methods of the Invention
[0256] 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.
[0257] In addition, the invention relates to 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 (II) ##STR5## or a
pharmaceutically suitable salt or prodrug thereof, wherein X.sub.1
is a bond or is selected from --O--, --O-alkyl, --NR.sup.2-- and
--NR.sup.2-alkyl; A is selected from Ar.sup.1,
--Ar.sup.2--Y--Ar.sup.3 and Ar.sup.4; Ar.sup.1 is aryl; Ar.sup.2 is
selected from aryl and heteroaryl; Ar.sup.3 is selected from aryl
and heteroaryl; Ar.sup.4 is selected from heteroaryl and
heterocycle; Y is a bond or is selected from --O--, --S-- and
--NR.sup.3--; and R.sup.1, R.sup.2 and R.sup.3 are individually
selected from hydrogen and C.sub.1-C.sub.6 alkyl. Preferred
compounds are compounds of formula (I), which are within the scope
of formula (II). Preferred embodiments for compounds of formula
(II) are as described for compounds of formula (I).
[0258] 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 (II), wherein the condition
or disorder is selected from a memory disorder, cognitive disorder,
neurodegeneration, and neurodevelopmental disorder.
[0259] 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 (II), 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.
[0260] 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 (II), wherein the condition
or disorder is schizophrenia.
[0261] 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 (II) in combination with an
atypical antipsychotic.
[0262] 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 (II), 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, wound healing, and other complications associated
with diabetes.
[0263] 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.
[0264] Specific examples of compounds that can be useful for the
treatment or prevention of .alpha.7 nAChR-mediated diseases or
conditions include, but are not limited to, compounds described in
the Compounds of the Invention and also in the Examples, and also
compounds such as [0265]
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-benzamide; [0266]
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-3,5-dichloro-benzamide;
[0267]
N-(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-2-methoxy-benzamide;
[0268] 1-H-indole-3-carboxylic
acid(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide; [0269]
(4.alpha.,.beta.)-4-amino-N-[1-azaadamantan-4-yl]-5-chloro-2-methoxy
benzamide; [0270] 6-chloro-imidazo[1,2-a]pyridine-8-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)amide; and [0271]
3-ethyl-indolizine-1-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide.
[0272] Methods for preparing compounds useful in the method of the
invention also can be found in Iriepa, I, et al. J. Molec. Struct.
1999, 509, 105; Flynn, D. L., et al. BMCL 1992, 2, 1613; U.S. Pat.
No. 4,816,453; WO 94/00454; U.S. Pat. No. 5,280,028; U.S. Pat. No.
5,399,562; WO 92/15593; U.S. Pat. No. 5,260,303; U.S. Pat. No.
5,591,749; U.S. Pat. No. 5,434,151; and U.S. Pat. No.
5,604,239.
[0273] 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 and/or
cognition 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.
[0274] 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). 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.
[0275] 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).
[0276] 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). Thus, .alpha.7 ligands demonstrate potential in the
treatment schizophrenia.
[0277] 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.
[0278] 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 inflammation and pain.
[0279] 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.
[0280] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting memory,
cognition, neurodegeneration, neurodevelopment, and
schizophrenia.
[0281] 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.
[0282] 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.
[0283] 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.
[0284] 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
[0285] As used in the descriptions of the schemes and the examples,
certain abbreviations are intended to have the following meanings:
Ac for acetyl; Bu for n-butyl; Bn for benzyl; cat. for cataylst;
dba for dibenzylidene acetone; DMF for dimethyl formamide; EtOH for
ethanol; Et.sub.3N for triethylamine; EtOAc for ethyl acetate; HPLC
for high pressure liquid chromatography; .sup.iPr for isopropyl;
.sup.iPrOAc for isopropyl acetate; LAH for lithium aluminum
hydride; Me for methyl; MeOH for methanol; NBS for
N-bromosuccinimide; NMP for N-methylpyrrolidine; OAc for acetoxy;
ONF for nonaflate or --OSO.sub.2CF.sub.2CF.sub.2CF.sub.2CF.sub.3;
Pd/C for palladium on carbon; Ph for phenyl; Rh/C for rhodium on
carbon; .sup.tBu for tert-butyl; .sup.tBuO for tert-butoxide; and
THF for tetrahydrofuran.
[0286] 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.
[0287] 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. ##STR6##
[0288] As shown in Scheme 1, compounds of formula (I) which are
prepared as outlined in Becker, D. P.; Flynn, D. L., Synthesis,
1992, 1080, when treated with a carboxylic acid of formula (2)
utilizing conditions known to those skilled in the art which couple
carboxylic acids to amines to generate amides, will provide
compounds of formula (3) which are representative of compounds of
the present invention. Examples of conditions known to generate
amides from a mixture of a carboxylic acid and an amine include but
are not limited to adding a coupling reagent such as but not
limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC),
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU). The coupling reagents may be added as a solid, a solution
or as the reagent bound to a solid support resin. In addition to
the coupling reagents, auxiliary-coupling reagents may facilitate
the coupling reaction. Auxiliary coupling reagents that are often
used in the coupling reactions include but are not limited to
1-Hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole
hydrate (HOBT). The coupling reaction may be carried out in
solvents such as but not limited to THF, DMA dichloromethane, ethyl
acetate and the like. ##STR7##
[0289] As shown in Scheme 2, the treatment of amines of formula (I)
with an isocyanate of formula (4) will provide compounds of formula
(5) which are representative of the compounds of the present
invention wherein X.sub.1 is --NR.sup.2-- and R.sup.2 is hydrogen.
The reaction may be carried out with or without a solvent for
example THF and DME. ##STR8##
[0290] As shown in Scheme 3, the treatment of amines of formula (I)
with reagents of general formula (Z.sub.1Z.sub.2)C.dbd.O, wherein
Z.sub.1 and Z.sub.2 are selected from chloro, imidazole,
succinimide and the like, followed by treatment with compounds of
general formula A-OH will provide compounds of formula (6) which
are representative of compounds of the present invention wherein
X.sub.1 is --O--. Compounds of general formula
(Z.sub.1Z.sub.2)C.dbd.O, may also be replaced with such reagents as
triphosgene and others known by one skilled in the art.
[0291] 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 Fumiss, Hannaford, Smith, and
Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE,
England.
[0292] The compounds of the invention have at least one basic
nitrogen whereby the compound can be treated with an acid to form a
desired salt. For example, a compound may be reacted with an acid
at or above room temperature to provide the desired salt, which is
deposited, and collected by filtration after cooling. Examples of
acids suitable for the reaction include, but are not limited to
tartaric acid, lactic acid, succinic acid, as well as mandelic,
atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic,
naphthalenesulfonic, carbonic, fumaric, gluconic, acetic,
propionic, salicylic, hydrochloric, hydrobromic, phosphoric,
sulfuric, citric, or hydroxybutyric acid, camphorsulfonic, malic,
phenylacetic, aspartic, glutamic, and the like.
Compositions of the Invention
[0293] 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.
[0294] 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 and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other 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.
[0295] 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.
[0296] 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.
[0297] 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.
[0298] 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.
[0299] 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.
[0300] 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.
[0301] 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.
[0302] 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.
[0303] 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.
[0304] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0305] 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.
[0306] 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.
[0307] 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.
[0308] 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.
[0309] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0310] 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.
[0311] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0312] 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.
[0313] Compounds of the invention also can be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0314] 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.
[0315] 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.
[0316] 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 use.
[0317] 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.
[0318] 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-hydroxyethansulfonate (isethionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate.
[0319] 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.
[0320] 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.
[0321] 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.
[0322] 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.
[0323] 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.
[0324] 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).
[0325] The invention contemplates pharmaceutically active compounds
either chemically synthesized or formed by in vivo
biotransformation to compounds of formula (I).
[0326] 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
Procedure for Amide Formation
Method A
[0327] A suspension of (4s)- or
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride (60
mg, 0.32 mmol; prepared according to Becker, D. P.; Flynn, D. L.
Synthesis 1992, 1080) and the carboxylic acid (1 equiv) in
anhydrous THF (2 mL) was treated with N,N-diisopropylethylamine
(iPr.sub.2NEt; 120 .mu.L, 0.93 mmol, 2.9 equiv; Acros) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU; 130 mg, 0.34 mmol, 1.1 equiv; Aldrich).
The mixture was stirred overnight, diluted with methanol (5 mL) and
filtered. The filtrate was concentrated in vacuo and the resulting
material was purified by preparative HPLC [Waters XTerra RP.sub.18
30.times.100 mm column, flow rate 40 mL/min, 5-95% gradient of
acetonitrile in buffer (0.1 M aq. ammonium bicarbonate, adjusted to
pH 10 with sodium hydroxide)] to afford the desired amide product
as its free base. Alternatively, the compound was purified on a
Waters Symmetry C.sub.8-30.times.100 mm column (flow rate 40
mL/min, 5-95% gradient of acetonitrile in 0.1% aqueous
trifluoroacetic acid) to afford the amide product as its
trifluoroacetate salt after evaporation of solvent.
Procedure for Amide Formation
Method B
[0328] A Smith Process vessel (0.5-2 mL) containing a stir bar was
charged with polymer-bound N-benzyl-N'-cyclohexylcarbodiimide
(PS-DCC; 3 equiv; Argonaut) followed by the carboxylic acid (1.1
equiv), N,N-diisopropylethylamine (iPr.sub.2NEt; 3 equiv; Aldrich),
and solutions of 1-hydroxybenzotriazole (HOBt; 1 equiv; Aldrich)
and (4s)-1-azatricyclo[3.3.1.1.sup.37]dec-4-ylamine (17.5 mg, 1
equiv; prepared according to Becker, D. P.; Flynn, D. L. Synthesis
1992, 1080) in N,N-dimethylacetamide (DMA). The reaction vessel was
then sealed and heated at 100.degree. C. in a microwave for
420-600s. After cooling, the reaction vessel was uncapped and the
mixture filtered through a column packed with Si-Carbonate
(polymer-bound carbonate, Silicycle; 2 g), eluting with methanol.
The filtrate was collected, dried, and purified by reverse-phase
HPLC to afford the desired product.
Procedure for Salt Formation
Method C
[0329] A rapidly stirring solution of the amide free base (from the
previous step) in ethyl acetate or ethyl acetate-ethanol (1:1) was
treated with either HCl-dioxane (1-2 equiv, 4 M; Aldrich)
orp-toluenesulfonic acid monohydrate (1 equiv; Aldrich) at room
temperature. After stirring for 2 hours, the precipitate was
collected by filtration and dried to afford the title compound.
Example 1
Benzo[b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0330] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thianaphthene-2-carboxylic acid (Aldrich) according to methods A
and C; yield 55 mg, 0.16 mmol (50%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.08-2.29 (m, 5H), 2.49 (s, 2H), 3.50 (d, J=13
Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.28 (t, J=3 Hz, 1H),
7.38-7.50 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (d, J=1 Hz, 1H); MS
(DCI/NH.sub.3) m/z 313 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS.HCl.0.3H.sub.2O: C, H, N.
Example 2
Benzo[b]thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0331] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thianaphthene-2-carboxylic acid (Aldrich) according to methods A
and C; yield 57 mg, 0.16 mmol (50%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1H), 2.36 (d,
J=14 Hz, 2H), 2.49 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=2 Hz, 4H),
4.42 (s, 1H), 7.39-7.50 (m, 2H), 7.88-7.96 (m, 2H), 8.12 (s, 1H);
MS (DCI/NH.sub.3) m/z 313 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS.HCl 0.12H.sub.2O: C, H, N.
Example 3
Benzo[b]thiophene-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0332] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
1-benzothiophene-3-carboxylic acid (Maybridge) according to methods
A and C; yield 60 mg, 0.17 mmol (56%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.10-2.30 (m, 5H), 2.48 (s, 2H), 3.50 (d, J=13
Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.33 (s, 1H),
7.36-7.49 (m, 2H), 7.91-7.96 (m, 1H), 8.28-8.34 (m, 2H); MS
(DCI/NH.sub.3) m/z 313 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS.HCl.0.17H.sub.2O: C, H, N.
Example 4
Benzo[b]thiophene-3-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0333] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
1-benzothiophene-3-carboxylic acid (Maybridge) according to methods
A and C; yield 58 mg, 0.17 mmol (56%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1H), 2.36 (d,
J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.69 (d, J=2 Hz, 4H),
4.47 (s, 1H), 7.38-7.48 (m, 2H), 7.92-7.96 (m, 1H), 8.27 (s, 1H),
8.27-8.32 (m, 1H); MS (DCI/NH.sub.3) m/z 313 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS HCl 0.13H.sub.2O: C, H, N.
Example 5
Benzo[b]thiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0334] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-benzothiophene-3-carboxylic acid (Maybridge) according to methods
A and C; yield 76 mg, 0.21 mmol (66%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.09-2.29 (m, 5H), 2.49 (s, 2H), 3.45-3.59 (m,
4H), 3.85 (d, J=13 Hz, 2H), 4.31 (s, 1H), 7.49 (d, J=5 Hz, 1H),
7.70 (d, J=5 Hz, 1H), 7.84 (dd, J=8, 2 Hz, 1H), 8.01 (d, J=8 Hz,
1H), 8.40 (d, J=2 Hz, 1H); MS (DCI/NH.sub.3) m/z 313 (M+H).sup.+;
Anal. C.sub.18H.sub.20N.sub.2OS.HCl-0.75H.sub.2O: C, H, N.
Example 6
Benzo[b]thiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0335] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-benzothiophene-3-carboxylic acid (Maybridge) according to methods
A and C; yield 64 mg, 0.18 mmol (56%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.98 (d, J=14 Hz, 2H), 2.21 (s, 1H), 2.37 (d,
J=14 Hz, 2H), 2.49 (s, 2H), 3.57 (s, 2H), 3.69 (d, J=1 Hz, 4H),
4.44 (s, 1H), 7.50 (d, J=5 Hz, 1H), 7.70 (d, J=6 Hz, 1H), 7.81 (dd,
J=8, 2 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 8.37 (d, J=2 Hz, 1H); MS
(DCI/NH.sub.3) m/z 313 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS.HCl.0.22H.sub.2O: C, H, N.
Example 7
1H-Indole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0336] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
indole-5-carboxylic acid (Aldrich) according to methods A and C;
yield 77 mg, 0.23 mmol (65%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 2.00-2.31 (m, 5H), 2.48 (s, 2H), 3.49 (d, J=12 Hz, 2H),
3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.31 (d, 1H), 6.57 (d, J=3 Hz,
1H), 7.33 (d, J=3 Hz, 1H), 7.44 (d, J=9 Hz, 1H), 7.66 (dd, J=9, 2
Hz, 1H), 8.18 (d, J=2 Hz, 1H); MS (DCI/NH.sub.3) m/z 296
(M+H).sup.+; Anal. C.sub.18H.sub.21N.sub.3O.HCl.0.1H.sub.2O: C, H,
N.
Example 8
1H-Indole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0337] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
indole-5-carboxylic acid (Aldrich) according to methods A and C;
yield 27 mg, 0.08 mmol (37%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 1.97 (d, J=13 Hz, 2H), 2.21 (s, 1H), 2.37 (d, J=14 Hz, 2H),
2.49 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 4.42 (s, 1H), 6.57 (dd,
J=3, 1 Hz, 1H), 7.34 (d, J=3 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.64
(dd, J=9, 2 Hz, 1H), 8.10-8.17 (m, 2H); MS (DCI/NH.sub.3) m/z 296
(M+H).sup.+; Anal. C.sub.18H.sub.21N.sub.3O.HCl.0.5H.sub.2O: C, H,
N.
Example 9
1H-Indole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0338] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
indole-6-carboxylic acid (Lancaster) according to methods A and C;
yield 59 mg, 0.17 mmol (48%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 2.12-2.30 (m, 6H), 2.49 (s, 2H), 3.49 (d, J=12 Hz, 2H),
3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.41 (d, J=3 Hz,
1H), 7.55 (dd, J=8, 2 Hz, 1H), 7.62 (d, J=12 Hz, 1H), 7.94-8.04 (m,
1H), 8.22 (d, J=5 Hz, 1H); MS (DCI/NH.sub.3) m/z 296 (M+H).sup.+;
Anal. C.sub.18H.sub.21N.sub.3O.HCl.0.75H.sub.2O: C, H, N.
Example 10
1H-Indole-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0339] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
indole-6-carboxylic acid (Lancaster) according to methods A and C;
yield 91 mg, 0.25 mmol (69%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 1.98 (d, J=13 Hz, 2H), 2.21 (s, 1H), 2.36 (d, J=13 Hz, 2H),
2.49 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 4.42 (s, 1H), 6.52 (dd,
J=3, 1 Hz, 1H), 7.41 (d, J=3 Hz, 1H), 7.52 (dd, J=8, 2 Hz, 1H),
7.63 (dd, J=8, 1 Hz, 1H), 7.93-7.99 (m, 1H); MS (DCI/NH.sub.3) m/z
296 (M+H).sup.+; Anal.
C.sub.18H.sub.21N.sub.3O.HCl.1.1H.sub.2O.0.2C.sub.4H.sub.8O.sub.2:
C, H, N.
Example 11
Thieno[2,3-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0340] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thieno[2,3-c]pyridine-5-carboxylic acid (Tetrahedron Lett. 1999,
40, 7935) according to methods A and C; yield 73 mg, 0.18 mmol
(51%): .sup.1H NMR (300 MHz, methanol-d4) .delta. 2.12-2.33 (m,
5H), 2.55 (s, 2H), 3.53 (d, J=12 Hz, 2H), 3.59 (s, 2H), 3.99 (d,
J=13 Hz, 2H), 4.40 (s, 1H), 7.94 (d, J=5 Hz, 1H), 8.65 (d, J=5 Hz,
1H), 9.15 (s, 1H), 9.59 (s, 1H); MS (DCI/NH.sub.3) m/z 296
(M+H).sup.+; Anal. C.sub.17H.sub.19N.sub.3OS.2.HCl.0.6H.sub.2O: C,
H, N.
Example 12
Thieno[2,3-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0341] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thieno[2,3-c]pyridine-5-carboxylic acid (Tetrahedron Lett. 1999,
40, 7935) according to methods A and C; yield 82 mg, 0.21 mmol
(59%): .sup.1H NMR (300 MHz, methanol-d4) .delta. 2.03 (d, J=14 Hz,
2H), 2.25 (s, 1H), 2.39 (d, J=14 Hz, 2H), 2.55 (s, 2H), 3.61 (s,
2H), 3.72 (s, 4H), 4.54 (s, 1H), 7.91 (d, J=5 Hz, 1H), 8.62 (d, J=5
Hz, 1H), 9.01 (s, 1H), 9.57 (s, 1H); MS (DCI/NH.sub.3) m/z 314
(M+H).sup.+; Anal. C.sub.17H.sub.19N.sub.3OS.2HCl.1.0H.sub.2O: C,
H, N.
Example 13
Thieno[3,2-c]pyridine-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0342] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thieno[3,2-c]pyridine-6-carboxylic acid (Tetrahedron Lett. 1999,
40, 7935) according to methods A and C; yield 69 mg, 0.18 mmol
(55%): .sup.1H NMR (300 MHz, methanol-d4) .delta. 2.06-2.33 (m,
5H), 2.55 (s, 2H), 3.53 (d, J=13 Hz, 2H), 3.59 (s, 2H), 3.98 (d,
J=13 Hz, 2H), 4.40 (s, 1H), 7.98 (d, J=5 Hz, 1H), 8.34 (d, J=5 Hz,
1H), 9.37 (s, 1H), 9.44 (s, 1H); MS (DCI/NH.sub.3) m/z 314
(M+H).sup.+; Anal. C.sub.17H.sub.19N.sub.3OS.2HCl.1.5H.sub.2O: C,
H, N.
Example 14
Thieno[3,2-c]pyridine-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride (78299-38, A-873053.3)
[0343] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thieno[3,2-c]pyridine-6-carboxylic acid (Tetrahedron Lett. 1999,
40, 7935) according to methods A and C; yield 111 mg, 0.21 mmol
(73%): .sup.1H NMR (300 MHz, methanol-d4) .delta. 2.03 (d, J=13 Hz,
2H), 2.25 (s, 1H), 2.37 (d, J=14 Hz, 2H), 2.54 (s, 2H), 3.60 (s,
2H), 3.72 (s, 4H), 4.54 (s, 1H), 7.92 (d, J=5 Hz, 1H), 8.27 (d, J=6
Hz, 1H), 9.17 (s, 1H), 9.39 (s, 1H); MS (DCI/NH.sub.3) m/z 314
(M+H).sup.+; Anal. C.sub.17H.sub.19N.sub.3OS.2HCl.2.2H.sub.2O: C,
H, N.
Example 15
Benzothiazole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0344] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
benzothiazole-6-carboxylic acid (Maybridge); yield 129 mg, 0.33
mmol (91%) according to methods A and C: .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.10-2.30 (m, 6H), 2.50 (s, 2H), 3.51 (d, J=12
Hz, 2H), 3.57 (s, 2H), 3.87 (d, J=13 Hz, 2H), 4.31 (s, 1H), 8.08
(dd, J=9, 2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.69 (d, J=2 Hz, 1H),
9.49 (s, 1H); MS (DCI/NH.sub.3) m/z 314 (M+H).sup.+; Anal.
C.sub.17H.sub.19N.sub.3OS.2HCl.0.4H.sub.2O: C, H, N.
Example 16
Benzothiazole-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0345] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
benzothiazole-6-carboxylic acid (Maybridge); yield 99 mg, 0.28 mmol
(77%) according to methods A and C: .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.99 (d, J=14 Hz, 2H), 2.22 (s, 1H), 2.37 (d,
J=14 Hz, 2H), 2.50 (s, 2H), 3.59 (s, 2H), 3.70 (s, 4H), 4.45 (s,
1H), 8.03 (dd, J=8, 2 Hz, 1H), 8.16 (d, J=8 Hz, 1H), 8.62 (d, J=2
Hz, 1H), 9.41 (s, 1H); MS (DCI/NH.sub.3) m/z 314 (M+H).sup.+; Anal.
C.sub.17H.sub.19N.sub.3OS.HCl0.3H.sub.2O: C, H, N.
Example 17
2-Methyl-1H-benzoimidazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0346] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-methyl-1H-benzimidazole-5-carboxylic acid (Acros) according to
methods A and C; yield 83 mg, 0.21 mmol (58%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.02-2.31 (m, 5H), 2.50 (s, 2H), 2.89 (s,
3H), 3.50 (d, J=13 Hz, 2H), 3.57 (s, 2H), 3.92 (d, J=13 Hz, 2H),
4.32 (s, 1H), 7.82 (d, J=9 Hz, 1H), 8.11 (dd, J=9, 2 Hz, 1H), 8.33
(s, 1H), 8.57 (d, J=5 Hz, 1H); MS (DCI/NH.sub.3) m/z 311
(M+H).sup.+; Anal. C.sub.18H.sub.22N.sub.4O.sub.2HCl1.0H.sub.2O: C,
H, N.
Example 18
2-Methyl-1H-benzoimidazole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0347] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-methyl-1H-benzimidazole-5-carboxylic acid (Acros) according to
methods A and C; yield 84 mg, 0.21 mmol (58%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 1.99 (d, J=13 Hz, 2H), 2.30-2.46 (m, 3H),
2.51 (s, 2H), 2.90 (s, 3H), 3.59 (s, 2H), 3.69 (s, 4H), 4.45 (s,
1H), 7.82 (dd, J=9, 1 Hz, 1H), 8.07 (dd, J=8, 1 Hz, 1H), 8.25 (dd,
J=1, 1 Hz, 1H), 8.50 (d, J=5 Hz, 1H); MS (DCI/NH.sub.3) m/z 311
(M+H).sup.+; Anal. C.sub.18H.sub.22N.sub.4O.sub.2HCl 1.0H.sub.2O:
C, H,N.
Example 19
2-Aminobenzothiazole-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
bis(trifluoroacetate)
[0348] The protected amide
[6-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylcarbamoyl)-benzothiazol-2-yl)-c-
arbamic acid tert-butyl ester] was prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-N-Boc-amino-4-benzothiazole-6-carboxylic acid (Astatech)
according to method A. The resulting material was dissolved in
dichloromethane (4 mL), treated with
dichloromethane-trifluoroacetic acid (4 mL, 1:1), and stirred
overnight. After concentrating the reaction mixture under a
nitrogen stream, the residue was triturated with ether, and washed
with ether and ethyl acetate to afford the title compound; yield 20
mg, 0.03 mmol (43%): .sup.1H NMR (300 MHz, methanol-d4) .delta.
2.05-2.31 (m, 5H), 2.46 (s, 2H), 3.41-3.61 (m, 4H), 3.83 (d, J=13
Hz, 2H), 4.27 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.88 (d, J=8 Hz, 1H),
8.23 (s, 1H); MS (DCI/NH.sub.3) m/z 329 (M+H).sup.+; Anal.
C.sub.17H.sub.20N.sub.4OS.2C.sub.2HF.sub.3O.sub.2: C, H, N.
Example 20
5-Chlorothiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0349] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-chlorothiophene-2-carboxylic acid (Aldrich) according to methods
A and C; yield 62 mg, 0.19 mmol (59%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.05-2.26 (m, 5H), 2.43 (s, 2H), 3.47 (d, J=13
Hz, 2H), 3.54 (s, 2H), 3.78 (d, J=13 Hz, 2H), 4.21 (t, J=3 Hz, 1H),
7.04 (d, J=4 Hz, 1H), 7.70 (d, J=4 Hz, 1H); MS (DCI/NH.sub.3) m/z
297, 299 (M+H).sup.+; Anal. C.sub.14H.sub.17ClN.sub.2OS.HCl: C, H,
N.
Example 21
5-Chlorothiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0350] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-chlorothiophene-2-carboxylic acid (Aldrich) according to methods
A and C; yield 56 mg, 0.17 mmol (53%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.95 (d, J=14 Hz, 2H), 2.17 (s, 1H), 2.29 (d,
J=14 Hz, 2H), 2.43 (s, 2H), 3.55 (s, 2H), 3.64 (d, J=2 Hz, 4H),
4.34 (s, 1H), 7.04 (d, J=4 Hz, 1H), 7.69 (d, J=4 Hz, 1H); MS
(DCI/NH.sub.3) m/z 297, 299 (M+H).sup.+; Anal.
C.sub.14H.sub.17ClN.sub.2OS.HCl 0.1H.sub.2O: C, H, N.
Example 22
4-Phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0351] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
4-phenylthiophene-2-carboxylic acid (Oakwood) according to methods
A and C; yield 54 mg, 0.14 mmol (44%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.86-1.98 (m, 2H), 2.06 (d, J=13 Hz, 3H),
2.24 (s, 2H), 3.35 (d, J=9 Hz, 4H), 3.84 (d, J=13 Hz, 2H),
4.10-4.20 (m, 1H), 7.26-7.36 (m, 1H), 7.43 (t, J=7 Hz, 2H),
7.69-7.78 (m, 2H), 8.08 (d, J=1 Hz, 1H), 8.45 (d, J=6 Hz, 1H), 8.54
(d, J=1 Hz, 1H); MS (DCI/NH.sub.3) m/z 339 (M+H).sup.+; Anal.
C.sub.20H.sub.22N.sub.2OS.HCl 0.07H.sub.2O: C, H, N.
Example 23
4-Phenylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0352] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
4-phenylthiophene-2-carboxylic acid (Oakwood) according to methods
A and C; yield 65 mg, 0.17 mmol (53%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.98 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.37 (d,
J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=1 Hz, 4H),
4.40 (s, 1H), 7.26-7.36 (m, 1H), 7.42 (t, J=7 Hz, 2H), 7.65-7.74
(m, 2H), 7.89 (d, J=1 Hz, 1H), 8.27 (d, J=2 Hz, 1H); MS
(DCI/NH.sub.3) m/z 339 (M+H).sup.+; Anal.
C.sub.20H.sub.22N.sub.2OS.HCl 0.5H.sub.2O: C, H, N.
Example 24
5-Phenylthiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0353] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-phenylthiophene-2-carboxylic acid (Maybridge) according to
methods A and C; yield 62 mg, 0.17 mmol (53%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.08-2.27 (m, 5H), 2.47 (s, 2H), 3.48 (d,
J=13 Hz, 2H), 3.55 (s, 2H), 3.81 (d, J=13 Hz, 2H), 4.25 (t, J=3 Hz,
1H), 7.32-7.47 (m, 4H), 7.65-7.71 (m, 2H), 7.83 (d, J=4 Hz, 1H); MS
(DCI/NH.sub.3) m/z 339 (M+H).sup.+; Anal.
C.sub.20H.sub.22N.sub.2OS.HCl: C, H, N.
Example 25
5-Phenylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0354] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-phenylthiophene-2-carboxylic acid (Maybridge) according to
methods A and C; yield 67 mg, 0.18 mmol (82%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 1.97 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.33
(d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=2 Hz, 4H),
4.39 (s, 1H), 7.32-7.47 (m, 4H), 7.66-7.72 (m, 2H), 7.83 (d, J=4
Hz, 1H); MS (DCI/NH.sub.3) m/z 339 (M+H).sup.+; Anal.
C.sub.20H.sub.22N.sub.2OS.HCl: C, H, N.
Example 26
5-(Pyridin-2-yl)-thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0355] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-(2-pyridyl)thiophene-2-carboxylic acid (Maybridge) according to
methods A and C; yield 35 mg, 0.09 mmol (43%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.07-2.29 (m, 5H), 2.48 (s, 2H), 3.49 (d,
J=12 Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.26 (s, 1H),
7.29-7.39 (m, 1H), 7.71 (d, J=4 Hz, 1H), 7.83-7.91 (m, 3H),
8.50-8.56 (m, 1H); MS (DCI/NH.sub.3) m/z 340 (M+H).sup.+; Anal.
C.sub.19H.sub.21N.sub.3OS.HCl.0.5H.sub.2O: C, H, N.
Example 27
5-(Pyridin-2-yl)-thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0356] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-(2-pyridyl)thiophene-2-carboxylic acid (Maybridge) according to
methods A and C; yield 49 mg, 0.14 mmol (66%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 1.98 (d, J=14 Hz, 2H), 2.21 (s, 1H), 2.34
(d, J=14 Hz, 2H), 2.50 (s, 2H), 3.58 (s, 2H), 3.68 (s, 4H), 4.41
(s, 1H), 7.75 (dt, J=7, 6, 1 Hz, 1H), 7.92 (d, J=4 Hz, 1H), 8.00
(d, J=4 Hz, 1H), 8.21 (d, J=8 Hz, 1H), 8.34 (dt, J=8, 2 Hz, 1H),
8.69 (d, J=5 Hz, 1H); MS (DCI/NH.sub.3) m/z 340 (M+H).sup.+; Anal.
C.sub.21H.sub.21F.sub.3N.sub.2O.sub.2.2HCl.0.2H.sub.2O.0.1C.sub.4H.sub.8O-
.sub.2: C, H, N.
Example 28
2,2'-Bithiophene-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0357] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2,2'-bithiophene-5-carboxylic acid (Acros) according to methods A
and C; yield 142 mg, 0.37 mmol (93%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.06-2.27 (m, 5H), 2.46 (s, 2H), 3.49 (d, J=13
Hz, 2H), 3.55 (s, 2H), 3.82 (d, J=13 Hz, 2H), 4.24 (s, 1H), 7.08
(dd, J=5, 4 Hz, 1H), 7.24 (d, J=4 Hz, 1H), 7.35 (dd, J=4, 1 Hz,
1H), 7.43 (dd, J=5, 1 Hz, 1H), 7.79 (d, J=4 Hz, 1H); MS
(DCI/NH.sub.3) m/z 345 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS.sub.2.HCl: C, H, N.
Example 29
2,2'-Bithiophene-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0358] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2,2'-bithiophene-5-carboxylic acid (Acros) according to methods A
and C; yield 105 mg, 0.27 mmol (76%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.97 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d,
J=14 Hz, 2H), 2.47 (s, 2H), 3.56 (s, 2H), 3.66 (s, 4H), 4.37 (s,
1H), 7.08 (dd, J=5, 4 Hz, 1H), 7.24 (d, J=4 Hz, 1H), 7.35 (dd, J=4,
1 Hz, 1H), 7.43 (dd, J=5, 1 Hz, 1 H), 7.78 (d, J=4 Hz, 1H); MS
(DCI/NH.sub.3) m/z 345 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.2OS.sub.2.HCl: C, H, N.
Example 30
5-(3-Trifluoromethylphenyl)-furan-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0359] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-[3-(trifluoromethyl)phenyl]-2-furoic acid (Aldrich) according to
methods A and C; yield 29 mg, 0.07 mmol (31%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.09-2.30 (m, 5H), 2.52 (s, 2H), 3.50 (d,
J=13 Hz, 2H), 3.57 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.28 (s, 1H),
7.12 (d, J=4 Hz, 1H), 7.34 (d, J=4 Hz, 1H), 7.63-7.69 (m, 2H),
8.10-8.18 (m, 1H), 8.24 (s, 1H); MS (DCI/NH.sub.3) m/z 391
(M+H).sup.+; Anal. C.sub.21H.sub.21F.sub.3N.sub.2O.sub.2.HCl
0.9H.sub.2O: C, H, N.
Example 31
5-(3-Trifluoromethylphenyl)-furan-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0360] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-[3-(trifluoromethyl)phenyl]-2-furoic acid (Aldrich) according to
methods A and C; yield 44 mg, 0.11 mmol (51%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 1.99 (d, J=14 Hz, 2H), 2.22 (s, 1H), 2.34
(d, J=14 Hz, 2H), 2.52 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 4.43
(s, 1H), 7.12 (d, J=4 Hz, 1H), 7.34 (d, J=4 Hz, 1H), 7.64-7.69 (m,
2H), 8.11-8.17 (m, 1H), 8.24 (s, 1H); MS (DCI/NH.sub.3) m/z 391
(M+H).sup.+; Anal. C.sub.21H.sub.21F.sub.3N.sub.2O.sub.2.HCl: C, H,
N.
Example 32
5-(2-Nitrophenyl)-furan-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0361] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-(2-nitrophenyl)-2-furoic acid (Aldrich) according to methods A
and C; yield 87 mg, 0.21 mmol (58%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.05-2.28 (m, 5H), 2.45 (s, 2H), 3.50 (s, 1H),
3.52-3.60 (m, 3H), 3.77 (d, J=13 Hz, 2H), 4.26 (s, 1H), 6.91 (d,
J=4 Hz, 1H), 7.29 (d, J=3 Hz, 1H), 7.62 (dt, J=8, 2 Hz, 1H), 7.74
(dt, J=8, 1 Hz, 1H), 7.85 (dd, J=8, 1 Hz, 1H), 7.94 (dd, J=8, 1 Hz,
1H); MS (DCI/NH.sub.3) m/z 368 (M+H).sup.+; Anal.
C.sub.20H.sub.21N.sub.3O.sub.4.HCl.0.7H.sub.2O: C, H, N.
Example 33
5-(2-Nitrophenyl)-furan-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0362] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-(2-nitrophenyl)-2-furoic acid (Aldrich) according to methods A
and C; yield 86 mg, 0.21 mmol (59%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.01 (d, J=13 Hz, 2H), 2.19-2.37 (m, 3H), 2.43
(s, 2H), 3.58 (s, 2H), 3.67 (s, 4H), 4.42 (s, 1H), 6.97 (d, J=4 Hz,
1H), 7.28 (d, J=3 Hz, 1H), 7.62 (dt, J=8, 1 Hz, 1H), 7.73 (dt, J=8,
1 Hz, 1H), 7.82 (dd, J=8, 1 Hz, 1H), 7.93 (dd, J=8, 1 Hz, 1H); MS
(DCI/NH.sub.3) m/z 368 (M+H).sup.+; Anal.
C.sub.20H.sub.21N.sub.3O.sub.4.HCl.0.2H.sub.2O: C, H, N.
Example 34
2-(Pyridin-4-yl)-thiazole-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0363] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-(4-pyridyl)-1,3-thiazole-4-carboxylic acid (Maybridge) according
to methods A and C; yield 84 mg, 0.19 mmol (54%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.03 (d, J=14 Hz, 2H), 2.24 (s, 1H), 2.33
(d, J=14 Hz, 2H), 2.53 (s, 2H), 3.60 (s, 2H), 3.72 (s, 4H), 4.50
(s, 1 H), 8.40 (d, J=6 Hz, 1H), 8.68 (s, 1H), 8.69-8.77 (m, 2H),
8.97 (d, J=7 Hz, 2H); MS (DCI/NH.sub.3) m/z 341 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.4OS.2HCl.1.2H.sub.2O: C, H, N.
Example 35
2-(Pyridin-4-yl)-thiazole-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0364] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-(4-pyridyl)-1,3-thiazole-4-carboxylic acid (Maybridge) according
to methods A and C; yield 103 mg, 0.22 mmol (62%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.03 (d, J=15 Hz, 2H), 2.24 (s, 1H), 2.33
(d, J=14 Hz, 2H), 2.53 (s, 2H), 3.60 (s, 2H), 3.71 (s, 4H), 4.50
(s, 1 H), 8.40 (d, J=6 Hz, 1H), 8.70 (s, 1H), 8.72-8.80 (m, 2H),
8.94-9.04 (m, 2H); MS (DCI/NH.sub.3) m/z 341 (M+H).sup.+; Anal.
C.sub.18H.sub.20N.sub.4OS-2HCl.2.75H.sub.2O: C, H, N.
Example 36
2-(Thiophen-2-yl)-thiazole-4-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0365] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-(2-thienyl)-1,3-thiazole-4-carboxylic acid (Maybridge) according
to methods A and C; yield 103 mg, 0.25 mmol (62%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.04-2.32 (m, 3H), 2.51 (s, 2H), 2.51 (s,
2H), 3.46-3.62 (m, 4H), 3.82 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.18
(dd, J=5, 4 Hz, 1H), 7.65 (dd, J=5, 1 Hz, 1H), 7.64 (dd, J=5, 1 Hz,
1H), 7.72 (dd, J=4, 1 Hz, 1H), 8.21 (s, 1H); MS (DCI/NH.sub.3) m/z
346 (M+H).sup.+; Anal. C.sub.17H.sub.19N.sub.3OS.sub.2.2HCl: C, H,
N.
Example 37
5-(Thiophen-2-yl)-1H-pyrazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
dihydrochloride
[0366] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (Specs) according to
methods A and C; yield 34 mg, 0.08 mmol (33%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.09-2.29 (m, 6H), 2.45 (s, 2H), 3.49 (d,
J=13 Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.29 (s, 1H),
7.02 (s, 1H), 7.12 (dd, J=5, 4 Hz, 1H), 7.43 (dd, J=4, 1 Hz, 1H),
7.48 (dd, J=5, 1 Hz, 1H); MS (DCI/NH.sub.3) m/z 329 (M+H).sup.+;
Anal.
C.sub.17H.sub.20N.sub.4OS.2HCl.0.15H.sub.2O.0.05C.sub.4H.sub.8O.sub.2:
C, H, N.
Example 38
N-[(4r)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-(thiophen-2-yl)-benzamid-
e tosylate
[0367] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
4-(2-thienyl)benzoic acid (Maybridge) according to methods A and C;
yield 156 mg, 0.30 mmol (75%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 2.08-2.27 (m, 6H), 2.35 (s, 3H), 2.47 (s, 2H), 3.49 (d,
J=12 Hz, 2H), 3.56 (s, 2H), 3.84 (d, J=13 Hz, 2H), 4.27 (s, 1H),
7.13 (t, J=5, 3 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 7.46 (d, J=5 Hz,
1H), 7.51 (d, J=2 Hz, 1H), 7.66-7.76 (m, 4H), 7.90 (d, J=9 Hz, 2H);
MS (DCI/NH.sub.3) m/z 339 (M+H).sup.+; Anal.
C.sub.20H.sub.22N.sub.2OS.C.sub.7H.sub.8O.sub.3S.0.25H.sub.2O: C,
H, N.
Example 39
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-(thiophen-2-yl)-benzamid-
e tosylate
[0368] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
4-(2-thienyl)benzoic acid (Maybridge) according to methods A and C;
yield 133 mg, 0.26 mmol (65%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 1.96 (d, J=13 Hz, 2H), 2.19 (s, 1H), 2.28-2.39 (m, 5H),
2.47 (s, 2H), 3.57 (s, 2H), 3.67 (s, 4H), 4.40 (s, 1H), 7.13 (dd,
J=5, 4 Hz, 1H), 7.19-7.25 (m, 2H), 7.46 (dd, J=5, 1 Hz, 1H), 7.51
(dd, J=4, 1 Hz, 1H), 7.67-7.79 (m, 4H), 7.87 (d, J=8 Hz, 1H); MS
(DCI/NH.sub.3) m/z 339 (M+H).sup.+; Anal. C.sub.20H.sub.22N.sub.2OS
C.sub.7H.sub.8O.sub.3S.0.35H.sub.2O: C, H, N.
Example 40
N-[(4r)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3
4-dichlorobenzamide hydrochloride
[0369] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
3,4-dichlorobenzoic acid (Aldrich) according to methods A and C;
yield 39 mg, 0.10 mmol (49%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 2.06-2.27 (m, 6H), 2.46 (s, 2H), 3.48 (d, J=12 Hz, 2H),
3.55 (s, 2H), 3.81 (d, J=13 Hz, 2H), 4.25 (s, 1H), 7.65 (d, J=8 Hz,
1H), 7.80 (dd, 1H), 8.07 (d, J=2 Hz, 1H); MS (DCI/NH.sub.3) m/z 325
(M+H).sup.+; Anal. C.sub.16H.sub.18Cl.sub.2N.sub.2O.HCl.
0.4HCl.0.15C.sub.4H.sub.8O.sub.2: C, H, N.
Example 41
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3
4-dichlorobenzamide hydrochloride
[0370] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
3,4-dichlorobenzoic acid (Aldrich) according to methods A and C;
yield 49 mg, 0.15 mmol (69%): .sup.1H NMR (300 MHz, methanol-d4)
.delta. 1.96 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H),
2.46 (s, 2H), 3.57 (s, 2H), 3.67 (s, 4H), 4.39 (s, 1H), 7.65 (d,
J=8 Hz, 1H), 7.77 (dd, J=8, 2 Hz, 1H), 8.02 (d, J=2 Hz, 1H); MS
(DCI/NH.sub.3) m/z 325 (M+H).sup.+; Anal.
C.sub.16H.sub.18Cl.sub.2N.sub.2O.HCl: C, H, N.
Example 42
N-[(4r)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-chlorobenzamide
[0371] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
4-chlorobenzoic acid (Aldrich) according to method A; yield 29 mg,
0.07 mmol (33%): .sup.1H NMR (300 MHz, methanol-d4) .delta.
2.06-2.30 (m, 5H), 2.45 (s, 2H), 3.48 (d, J=12 Hz, 2H), 3.55 (s,
2H), 3.80 (d, J=12 Hz, 2H), 4.25 (s, 1H), 7.49 (d, J=9 Hz, 2H),
7.86 (d, J=9 Hz, 2H); MS (DCI/NH.sub.3) m/z 291 (M+H).sup.+; Anal.
C.sub.16H.sub.19Cl.sub.2N.sub.2O.HCl.0.45HCl: C, H, N.
Example 43
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-chlorobenzamide
hydrochloride
[0372] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
4-chlorobenzoic acid (Aldrich) according to methods A and C; yield
49 mg, 0.17 mmol (63%): .sup.1H NMR (300 MHz, methanol-d4) .delta.
1.96 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H), 2.46
(s, 2H), 3.57 (s, 2H), 3.67 (s, 4H), 4.39 (s, 1H), 7.49 (d, J=8 Hz,
2H), 7.83 (d, J=8 Hz, 2H); MS (DCI/NH.sub.3) m/z 291 (M+H).sup.+;
Anal. C.sub.16H.sub.19ClN.sub.2O.HCl: C, H, N.
Example 44
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-chlorobenzamide
[0373] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
3-chlorobenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.84-2.05 (m, 5H), 2.11 (s, 1H),
2.29 (s, 1H), 2.32 (s, 1H), 2.39 (s, 2H), 3.47-3.53 (m, 2H),
3.62-3.74 (m, 1H), 3.77-3.88 (m, 1H), 4.38 (s, 1H), 7.43-7.52 (m,
1H), 7.54-7.61 (m, 1H), 7.73-7.80 (m, 1H), 7.78-7.88 (m, 1H); MS
(APCI/NH.sub.3) m/z 291 (M+H).sup.+.
Example 45
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2,3-dichlorobenzamide
[0374] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
2,3-dichlorobenzoic acid (Aldrich) according to method B; .sup.1H
NMR (500 MHz, methanol-d4) .delta. 1.91-1.99 (m, 6H), 2.07 (d, 1H),
2.26 (d, J=13 Hz, 2H), 2.35 (s, 2H), 3.44-3.52 (m, 2H), 3.77-3.89
(m, 1H), 4.43 (s, 1H), 7.36-7.42 (m, 2H), 7.63 (dd, J=6, 4 Hz, 1H);
MS (APCI/NH.sub.3) m/z 325 (M+H).sup.+.
Example 46
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2,4-dichlorobenzamide
[0375] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
2,4-dichlorobenzoic acid (Aldrich) according to method B; .sup.1H
NMR (500 MHz, methanol-d4) .delta. 1.91-1.99 (m, 3H), 2.04 (s, 1H),
2.21-2.33 (m, 4H), 3.44 (s, 2H), 3.55 (s, 4H), 4.41 (s, 1H),
7.41-7.49 (m, 2H), 7.54-7.59 (m, 1H); MS (APCI/NH.sub.3) m/z 325
(M+H).sup.+.
Example 47
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-fluorobenzamide
[0376] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
4-fluorobenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.91-2.04 (m, 4H), 2.12 (s, 1H),
2.31 (d, J=14 Hz, 2H), 2.38 (s, 1H), 3.49 (s, 1H), 3.59 (s, 3H),
3.73 (s, 1H), 3.77-3.89 (m, 1H), 4.38 (s, 1H), 7.20 (t, J=9 Hz,
2H), 7.90 (dd, J=9, 5 Hz, 2H); MS (APCI/NH.sub.3) m/z 275
(M+H).sup.+.
Example 48
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-fluorobenzamide
[0377] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
3-fluorobenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.88-1.98 (m, 3H), 2.03 (s, 1H),
2.26-2.33 (m, 4H), 3.42 (s, 2H), 3.48-3.56 (m, 4H), 4.37 (s, 1H),
7.27-7.32 (m, 1H), 7.44-7.53 (m, 1H), 7.55-7.62 (m, 1H), 7.66 (d,
J=8 Hz, 1H); MS (APCI/NH.sub.3) m/z 275 (M+H).sup.+.
Example 49
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-hydroxybenzamide
[0378] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
4-hydroxybenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.91-1.98 (m, 5H), 2.14 (s, 1H),
2.27-2.34 (m, 2H), 2.36-2.43 (m, 1H), 3.50 (s, 2H), 3.60 (s, 3H),
4.36 (s, 1H), 6.70-6.98 (m, 2H), 7.56-7.82 (m, 2H); MS
(APCI/NH.sub.3) m/z 273 (M+H).sup.+.
Example 50
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-hydroxybenzamide
[0379] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
3-hydroxybenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.96 (s, 3H), 2.12 (s, 1H), 2.29 (d,
J=14 Hz, 2H), 2.38 (s, 2H), 3.49 (s, 2H), 3.59 (s, 3H), 3.74-3.91
(m, 1H), 4.36 (s, 1H), 6.90-7.06 (m, 1H), 7.18-7.25 (m, J=2 Hz,
1H), 7.24-7.31 (m, 2H); MS (APCI/NH.sub.3) m/z 273 (M+H).sup.+.
Example 51
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-methoxybenzamide
[0380] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
4-methoxybenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.92-1.99 (m, 4H), 2.12 (s, 1H),
2.31 (d, J=14 Hz, 2H), 2.39 (s, 1H), 3.50 (s, 2H), 3.60 (s, 3H),
3.84-3.87 (m, 3H), 4.37 (s, 1H), 6.97-7.03 (m, 2H), 7.75-7.88 (m,
2H); MS (APCI/NH.sub.3) m/z 287 (M+H).sup.+.
Example 52
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-methoxybenzamide
[0381] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
3-methoxybenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 2.30 (d, J=14 Hz, 6H), 2.40 (s, 2H),
3.49 (s, 2H), 3.60 (s, 3H), 3.79-3.89 (m, 4H), 4.38 (s, 1H), 7.13
(d, J=3 Hz, 1H), 7.33-7.44 (m, 3H); MS (APCI/NH.sub.3) m/z 287
(M+H).sup.+.
Example 53
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-2-ethoxybenzamide
[0382] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
2-ethoxybenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.53 (t, J=7 Hz, 3H), 1.94 (s, 1H),
2.02 (d, 2H), 2.11 (d, 1H), 2.20 (d, J=14 Hz, 2H), 2.32 (s, 2H),
3.48 (s, 2H), 3.59 (s, 4H), 4.28 (q, J=7 Hz, 2H), 4.47 (s, 1H),
7.06-7.10 (m, 1H), 7.17 (d, J=8 Hz, 1H), 7.48-7.53 (m, 1H), 7.96
(dd, J=8, 2 Hz, 1H); MS (APCI/NH.sub.3) m/z 301 (M+H).sup.+.
Example 54
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-3-trifluoromethoxybenzamid-
e
[0383] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
3-trifluoromethoxybenzoic acid (Aldrich) according to method B;
.sup.1H NMR (500 MHz, methanol-d4) .delta. 1.96 (d, J=13 Hz, 2H),
2.12 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.40 (s, 2H), 3.50 (s, 2H),
3.60 (s, 4H), 4.40 (s, 1H), 7.45-7.51 (m, 1H), 7.56-7.62 (m, 1H),
7.74 (s, 1H), 7.82-7.87 (m, 1H); MS (APCI/NH.sub.3) m/z 341
(M+H).sup.+.
Example 55
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-phenoxybenzamide
[0384] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
4-phenoxybenzoic acid (Aldrich) according to method B; .sup.1H NMR
(500 MHz, methanol-d4) .delta. 1.95 (d, J=13 Hz, 2H), 2.11 (s, 1H),
2.31 (d, J=13 Hz, 2H), 2.38 (s, 2H), 3.49 (s, 2H), 3.59 (s, 4H),
4.38 (s, 1H), 7.00-7.09 (m, 4H), 7.17-7.23 (m, 1H), 7.38-7.44 (m,
J=8, 8 Hz, 2H), 7.81-7.89 (m, 2H); MS (APCI/NH.sub.3) m/z 349
(M+H).sup.+.
Example 56
N-[(4s)-1-Azatricyclo[3.3.1.1.sup.3,7]dec-4-yl]-4-methylsulfanylbenzamide
[0385] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
4-(methylthio)benzoic acid (Aldrich) according to method B; .sup.1H
NMR (500 MHz, methanol-d4) .delta. 1.92-1.98 (m, 2H), 2.11 (s, 1H),
2.31 (d, J=14 Hz, 2H), 2.38 (s, 2H), 2.52 (s, 3H), 3.49 (s, 2H),
3.59 (s, 4H), 4.37 (s, 1H), 7.31-7.35 (m, 2H), 7.74-7.80 (m, 2H);
MS (APCI/NH.sub.3) m/z 287 (M+H).sup.+.
Example 57
Thiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
trifluoroacetate
[0386] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
2-thiophenecarboxylic acid (Aldrich) according to method B; .sup.1H
NMR (500 MHz, methanol-d4) .delta. 1.93 (m, 2H), 2.15-2.36 (m, 3H),
2.46 (s, 1H), 2.70 (s, 1H), 3.56 (s, 1H), 3.66 (s, 2H), 3.90 (s,
1H), 3.93 (d, 1H), 4.03 (d, 1H), 4.38 (s, 1H), 7.11-7.18 (m, 1H),
7.65-7.71 (m, 1H), 7.81-7.86 (m, 1H); MS (DCI/NH.sub.3) m/z 263
(M+H).sup.+.
Example 58
5-Methylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
trifluoroacetate
[0387] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
5-methyl-2-thiophenecarboxylic acid (Aldrich) according to method
B; .sup.1H NMR (500 MHz, methanol-d4) .delta. 1.92 (dd, J=26, 13
Hz, 2H), 2.15-2.34 (m, 3H), 2.44 (s, 1H), 2.51 (s, 3H), 2.68 (s,
1H), 3.56 (s, 1H), 3.65 (s, 2H), 3.89 (s, 1H), 3.92 (d, 1H), 4.02
(d, 1H), 4.34 (s, 1H), 6.82 (dd, J=4, 1 Hz, 1H), 7.61-7.65 (m, 1H);
MS (DCI/NH.sub.3) m/z 277 (M+H).sup.+.
Example 59
3-Methylthiophene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
trifluoroacetate
[0388] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
3-methyl-2-thiophenecarboxylic acid (Aldrich) according to method
B; .sup.1H NMR (500 MHz, methanol-d4) .delta. ppm 1.87-2.00 (m,
J=26, 14 Hz, 2H), 2.15-2.29 (m, 3H), 2.44 (s, 1H), 2.46-2.51 (m,
J=3 Hz, 3H), 2.68 (s, 1H), 3.56 (s, 1H), 3.66 (d, J=2 Hz, 2H), 3.90
(s, 1H), 3.94 (d, 1H), 4.03 (d, 1H), 4.35-4.41 (m, 1H), 6.95 (d,
J=5 Hz, 1H), 7.47 (d, J=5 Hz, 1H); MS (DCI/NH.sub.3) m/z 277
(M+H).sup.+.
Example 60
Naphthalene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0389] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and 2-naphthoic
acid (Aldrich) according to method B; .sup.1H NMR (500 MHz,
methanol-d4) .delta. 1.94-2.03 (m, 3H), 2.29-2.40 (m, 4H), 3.40 (s,
2H), 3.51 (s, 4H), 4.43 (s, 1H), 7.54-7.62 (m, 2H), 7.86-8.02 (m,
4H), 8.40 (d, J=1 Hz, 1H); MS (APCI/NH.sub.3) m/z 307
(M+H).sup.+.
Example 61
1-Hydroxynaphthalene-2-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0390] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
1-hydroxy-2-naphthoic acid (Aldrich) according to method B; .sup.1H
NMR (500 MHz, methanol-d4) .delta. 1.95-2.04 (m, 2H), 2.15-2.27 (m,
1H), 2.33-2.46 (m, 3H), 2.56-2.64 (m, 1H), 3.48-3.90 (m, 6H),
4.42-4.53 (m, 1H), 7.05-7.28 (m, 1H), 7.37-7.57 (m, 2H), 7.67-7.78
(m, 1H), 7.81-7.90 (m, 1H), 8.34-8.44 (m, 1H); MS (APCI/NH.sub.3)
m/z 323 (M+H).sup.+.
Example 62
Naphthalene-1-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0391] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and 1-naphthoic
acid (Aldrich) according to method B; .sup.1H NMR (500 MHz,
methanol-d4) .delta. 1.94-2.71 (m, 7H), 3.46-3.93 (m, 6H), 4.56 (s,
1H), 7.50-7.59 (m, 3H), 7.61-7.68 (m, 1H), 7.90-7.96 (m, 1H),
7.97-8.03 (m, 1H), 8.11-8.18 (m, 1H); MS (APCI/NH.sub.3) m/z 307
(M+H).sup.+.
Example 63
6-Chloro-2H-chromene-3-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
trifluoroacetate
[0392] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and
6-chloro-2H-1-benzopyran-3-carboxylic acid (Acros) according to
method B; .sup.1H NMR (500 MHz, methanol-d4) .delta. 1.84-2.00 (m,
2H), 2.14-2.67 (m, 5H), 3.51-3.72 (m, 4H), 3.86-4.08 (m, 2H),
4.28-4.33 (m, 1H), 4.95 (t, J=2 Hz, 2H), 6.82 (d, J=8 Hz, 1H),
7.17-7.27 (m, 3H); MS (DCI/NH.sub.3) m/z 345 (M+H).sup.+.
Example 64
Benzo[,3]dioxole-5-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0393] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine and piperonylic
acid (Aldrich) according to method B; .sup.1H NMR (500 MHz,
methanol-d4) .delta. 1.86-2.63 (m, 7 H), 3.46-3.86 (m, 6H), 4.35
(s, 1H), 6.02-6.05 (m, 2H), 6.90 (d, J=8 Hz, 1H), 7.32 (d, J=2 Hz,
1H), 7.44 (dd, J=8, 2 Hz, 1H); MS (APCI/NH.sub.3) m/z 301
(M+H).sup.+.
Example 65
2,3-Dihydrobenzo[1,4]dioxine-6-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0394] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
1,4-benzodioxan-6-carboxylic acid (Maybridge) according to methods
A and C; yield 49 mg, 0.13 mmol (42%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 2.08-2.29 (m, 5H), 2.49 (s, 2H), 3.50 (d, J=13
Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.28 (s, 1H),
7.38-7.50 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (d, J=1 Hz, 1H); MS
(DCI/NH.sub.3) m/z 315 (M+H).sup.+; Anal.
C.sub.18H.sub.22N.sub.2O.sub.3.HCl.0.25NH.sub.4OH: C, H, N.
Example 66
2,3-Dihydrobenzo[1,4]dioxine-6-carboxylic
acid(4s)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0395] Prepared from
(4s)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
1,4-benzodioxan-6-carboxylic acid (Maybridge) according to methods
A and C; yield 49 mg, 0.14 mmol (43%): .sup.1H NMR (300 MHz,
methanol-d4) .delta. 1.94 (d, J=13 Hz, 2H), 2.18 (s, 2H), 2.30 (d,
J=14 Hz, 2H), 2.44 (s, 2H), 3.55 (s, 1H), 3.65 (d, J=2 Hz, 4H),
4.24-4.32 (m, 4H), 4.35 (s, 1H), 6.90 (ddd, J=9, 1 Hz, 1H),
7.33-7.39 (m, 2H); MS (DCI/NH.sub.3) m/z 315 (M+H).sup.+; Anal.
C.sub.18H.sub.22N.sub.2O.sub.3.HCl.0.25H.sub.2O: C, H, N.
Example 67
Furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0396] Prepared from 4r-amino-1-azaadamantane hydrochloride and
furo[2,3-c]pyridine-5-carboxylic acid (EP911335) according to
methods A and C; yield 67 mg, 0.14 mmol (37%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.10-2.29 (m, 5H), 2.36 (s, 3H), 2.52 (s,
2H), 3.51 (d, J=12.9 Hz, 2H), 3.57 (s, 2H), 3.92 (d, J=12.5 Hz,
2H), 4.35 (s, 1H), 7.20 (d, J=8.1 Hz, 2H), 7.29 (d, J=2.4 Hz, 1H),
7.67 (d, J=8.5 Hz, 2H), 8.44 (d, J=2.4 Hz, 1H), 8.81 (s, 1H), 9.16
(s, 1H). MS (DCI/NH.sub.3) m/z 298 (M+H).sup.+; Anal.
C.sub.17H.sub.19N.sub.3O.1.5 C.sub.7H.sub.8O.sub.3S.1.65H.sub.2O:
C, H, N
Example 68
3-Methyl-benzofuran-2-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0397] Prepared from 4r-amino-1-azaadamantane hydrochloride and
3-methyl-benzofuran-2-carboxylic acid (Aldrich) according to
methods A and C; yield 97 mg, 0.20 mmol (47%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.07-2.29 (m, 5H), 2.35 (s, 3H), 2.48 (s,
2H), 2.59 (s, 3H), 3.49 (d, J=12 Hz, 2H), 3.56 (s, 2H), 3.84 (d,
J=12 Hz, 2H), 4.30 (s, 1H), 7.21 (d, J=8 Hz, 2H), 7.33 (t, J=7 Hz,
1H), 7.47 (t, J=7 Hz, 1H), 7.51-7.58 (m, 1H), 7.70 (d, J=8 Hz, 2H);
MS (DCI/NH.sub.3) m/z 311 (M+H).sup.+; Anal.
C.sub.19H.sub.22N.sub.2O.sub.2.C.sub.7H.sub.8O.sub.3S.0.25H.sub.2O:
C, H, N
Example 69
Furo[2,3-c]pyridine-5-carboxylic acid
(1-aza-tricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
[0398] Prepared from 4s-amino-1-azaadamantane hydrochloride and
furo[2,3-c]pyridine-5-carboxylic acid (EP911335) according to
methods A and C; yield 71 mg, 0.15 mmol (36%): .sup.1H NMR (300
MHz, methanol-d4) .delta. 2.02 (d, J=13 Hz, 2H), 2.19-2.33 (m, 3H),
2.36 (s, 3H), 2.46 (s, 2H), 3.59 (s, 2H), 3.71 (s, 4H), 4.48 (s,
1H), 7.13 (d, J=2.4 Hz, 1H), 7.23 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz,
2H), 8.13 (d, J=2.4 Hz, 1H), 8.48 (s, 1H), 8.93 (s, 1H). MS
(DCI/NH.sub.3) m/z 298 (M+H).sup.+; Anal.
C.sub.17H.sub.19N.sub.3O.1.0C.sub.7H.sub.8O.sub.3S.0.75H.sub.2O: C,
H, N
Example 70
2-Naphthoic acid
(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0399] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
2-naphthoic acid according to methods A and C. .sup.1H NMR (300
MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H),
3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.51-7.67
(m, 2H), 7.85-8.07 (m, 4H), 8.46 (s, 1H). MS (DCI/NH.sub.3) m/z
308. Anal. Calculated for C.sub.20H.sub.22N.sub.2O.HCl: C, 70.06;
H, 6.76; N, 9.14. Found: C, 69.72; H, 6.58; N, 8.03.
Example 71
Benzofuran-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0400] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
benzofuran-2-carboxylic acid according to methods A and C. .sup.1H
NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H), 2.51 (s,
2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H),
7.29-7.38 (m, 1H), 7.44-7.52 (m, 1H), 7.57 (s, 1H), 7.61 (d, J=7.4
Hz, 1H), 7.74 (d, J=7.8 Hz, 1H). MS (DCI/NH.sub.3) m/z 297. Anal.
Calculated for C.sub.18H.sub.20N.sub.2O.sub.2HCl: C, 64.96; H,
6.36; N, 8.42. Found: C, 64.51; H, 6.23; N, 8.14.
Example 72
Benzo[d][1,2,3]thiadiazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0401] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
benzo[d][1,2,3]thiadiazole-5-carboxylic acid according to methods A
and C. .sup.1H NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m,
5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33
(s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H), 9.19 (s,
1H). MS (DCI/NH.sub.3) m/z 315. Anal. Calculated for
C.sub.16H.sub.18N.sub.4OS.HCl: C, 54.77; H, 5.46; N, 15.97. Found:
C, 53.27; H, 4.94; N, 15.47.
Example 73
Isoquinoline-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0402] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
isoquinoline-3-carboxylic acid according to methods A and C.
.sup.1H NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H),
2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s,
1H), 7.43 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.93 (d, J=1.4
Hz, 1H), 8.24 (d, J=1.7 Hz, 1H). MS (DCI/NH.sub.3) m/z 308. Anal.
Calculated for C.sub.19H.sub.21N.sub.3O.HCl: C, 66.37; H, 6.45; N,
12.22. Found: C, 47.6; H, 5.89; N, 8.71.
Example 74
Benzo[c][1,2,5]thiadiazole-5-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0403] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
benzo[c][1,2,5]thiadiazole-5-carboxylic acid according to methods A
and C. .sup.1H NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m,
5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33
(s, 1H), 7.90-8.51 (m, 1H), 8.98 (s, 1H), 9.57 (s, 1H). MS
(DCI/NH.sub.3) m/z 315. Anal. Calculated for
C.sub.16H.sub.18N.sub.4OS.HCl: C, 54.77; H, 5.46; N, 15.97. Found:
C, 53.82; H, 5.31; N, 16.17.
Example 75
5-(2-Methylthiazol-4-yl)thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0404] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-(2-methylthiazol-4-yl)thiophene-2-carboxylic acid according to
methods A and C. .sup.1H NMR (300 MHz, methanol-d4) .delta. ppm
2.08-2.34 (m, 5H), 2.51 (s, 2H), 2.74 (s, 3H), 3.42-3.64 (m, 4H),
3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.49 (d, J=4.1 Hz, 1H), 7.68
(s, 1H), 7.79 (d, J=4.1 Hz, 1H). MS (DCI/NH.sub.3) m/z 360.
Example 76
3-(Thiophen-2-yl)benzoic acid
(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0405] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
3-thiophen-2-yl)benzoic acid according to methods A and C. .sup.1H
NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H), 2.51 (s,
2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.13
(dd, J=5.1, 3.73 Hz, 1H), 7.43 (dd, J=5.1, 1.0 Hz, 1H), 7.47-7.55
(m, 2H), 7.80 (dd, J=16.6, 8.1 Hz, 2H), 8.11 (t, J=1.7 Hz, 1H). MS
(DCI/NH.sub.3) m/z 339.
Example 77
Thieno[3,2-b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0406] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thieno[3,2-b]thiophene-2-carboxylic acid according to methods A and
C. .sup.1H NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m,
5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33
(s, 1H), 7.37 (d, J=5.1 Hz, 1H), 7.71 (d, J=5.1 Hz, 1H), 8.12 (s,
1H). MS (DCI/NH.sub.3) m/z 319.
Example 78
Thieno[2,3-b]thiophene-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0407] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
thieno[2,3-b]thiophene-2-carboxylic acid according to methods A and
C. .sup.1H NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m,
5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33
(s, 1H), 7.32 (d, J=5.4 Hz, 1H), 7.53-7.58 (m, 1H), 8.06 (s, 1H).
MS (DCI/NH.sub.3) m/z 319. Anal. Calculated for
C.sub.16H.sub.18N.sub.2OS.sub.2.HCl: C, 54.15; H, 5.40; N, 7.89.
Found: C, 54.19; H, 5.25; N, 7.72.
Example 79
5-Chlorobenzofuran-2-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0408] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
5-chlorobenzofuran-2-carboxylic acid according to methods A and C.
.sup.1H NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H),
2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s,
1H), 6.43-6.48 (m, 1H), 6.52 (s, 1H), 6.57-6.62 (m, 1H), 6.76 (d,
J=2.0 Hz, 1H). MS (DCI/NH.sub.3) m/z 331.
Example 80
1H-Indazole-3-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0409] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
1H-indazole-3-carboxylic acid according to methods A and C. .sup.1H
NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H), 2.51 (s,
2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H),
7.23-7.32 (m, 1H), 7.40-7.48 (m, 1H), 7.57-7.63 (m, 1H), 8.20 (d,
J=8.1 Hz, 1H). MS (DCI/NH.sub.3) m/z 297.
Example 81
1H-Indazole-4-carboxylic
acid(4r)-(1-azatricyclo[3.3.1.1.sup.3,7]dec-4-yl)-amide
hydrochloride
[0410] Prepared from
(4r)-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylamine hydrochloride and
1H-indazole-4-carboxylic acid according to methods A and C. .sup.1H
NMR (300 MHz, methanol-d4) .delta. ppm 2.08-2.34 (m, 5H), 2.51 (s,
2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H),
7.42-7.52 (m, 1H), 7.58-7.64 (m, 1H), 7.72 (d, J=8.5 Hz, 1H), 8.33
(s, 1H). MS (DCI/NH.sub.3) m/z 297.
Determination of Biological Activity
[0411] 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
[0412] 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 CaCT.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.3B]-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.i values were calculated from the IC.sub.50s using
the Cheng-Prusoff equation, where
K.sub.i=IC.sub.50/(1+[Ligand]/K.sub.D).
[.sup.3H]-Methyllycaconitine (MLA) Binding
[0413] 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 [3H]-MLA (25
C.sub.i/mmol; Perkin Elmer/NEN Life Science Products, Boston,
Mass.) and 0.1% bovine serum albumin (BSA, Millipore, Bedford,
Mass.) were incubated in a final volume of 500 .mu.L for 60 minutes
at 22.degree. C. Seven log-dilution concentrations of each compound
were tested in duplicate. 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
[0414] [.sup.3H]-DPPB,
[.sup.3H]-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide, binding to the .alpha.7 nAChR subtype
was determined using membrane enriched fractions from rat brain
minus cerebellum or human cortex (ABS Inc., Wilmington, Del.).
Pellets were thawed at 4.degree. C., washed and resuspended with a
Polytron at a setting of 7 in 30 volumes of BSS-Tris buffer (120 mM
NaCl, 5 mM KCl, 2 mM CaCl.sub.2, 2 mM MgCl.sub.2, and 50 mM
Tris-Cl, pH 7.4, 4.degree. C.). Seven log-dilution concentrations
of test compounds containing 100-200 .mu.g of protein, and 0.5 nM
[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-3H]2,2-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-bicyclo-
[2.2.1]heptane; iodide Preparation
[0415]
[Methyl-3H]2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-
-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
[0416] 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
[0417] 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)
[0418] [.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)
[0419] 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.3B]-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
[0420] [.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.
[0421] The radiochemical purity of [.sup.3H]-DPPB was found to be
>98%. The specific activity was determined to be 62.78 Ci/mmol
by mass spectroscopy.
[0422] Other suitable radioligands are compounds of the formula
(III): ##STR9##
[0423] wherein:
[0424] m, n, and q each are independently 0, 1, or 2;
[0425] l and p each are independently 1 or 2;
[0426] the sum of l, m, n, p, and q is 3, 4, 5, or 6;
[0427] A.sub.III is selected from: ##STR10##
[0428] B is selected from substituted or unsubstituted phenyl.
[0429] Phenyl groups can be unsubstituted or substituted with one,
two, three, four, or five substituents independently selected from
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
arylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, cyano,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,
and nitro. Preferred compounds are those wherein the phenyl groups
is 3,4-(methylenedioxy)phenyl or phenyl substituted with 0, 1, 2,
or 3 substituents in the meta- or para-positions selected from
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
arylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, cyano,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,
and nitro.
[0430] Radiolabelled compounds of formula (III) can be prepared
from tertiary amines of Formula (IV) described in U.S. patent
application Ser. No. 10/666,884, filed Sep. 19, 2003, which
published as US20050065178A1, and U.S. patent application Ser. No.
10/942,035, filed Sep. 16, 2004, which published as US20050101602A1
by treating a desired tertiary amine with [.sup.3H]-methyl iodide
as illustrated below and as described above in Steps 3-5.
##STR11##
[0431] Methods for preparing compounds within the scope of formula
(IV) are described in U.S. patent application Ser. No. 10/666,884
and U.S. patent application Ser. No. 10/942,035, both of which are
incorporated by reference herein in their entirety.
[0432] Briefly, a bromide, 1,4-bromochloride, or 1,4-dichloride of
a desired aromatic nitrogen ring represented by AIII is coupled
with a desired diamine group under palladium coupling conditions,
for example Pd(0) and base or Pd(0),
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), and base. The
product obtained is further coupled with a boronic acid of a
desired substituted or unsubstituted phenyl group under suitable
palladium coupling conditions, for example Pd(0) and base. Methods
for preparing compounds of formula (IV) are further described in
US20050065178A1, which published on Mar. 24, 2005, and
US20050101602A1, which published on May 12, 2005.
[0433] The term "radiolabel" refers to a compound of the invention
in which at least one of the atoms is a radioactive atom or
radioactive isotope, wherein the radioactive atom or isotope
spontaneously emits gamma rays or energetic particles, for example
alpha particles or beta particles, or positrons. Examples of such
radioactive atoms include, but are not limited to, 3H (tritium),
.sup.14C, .sup.11C, .sup.15O, .sup.18F, .sup.35S, .sup.123I, and
.sup.125I.
[0434] Radiolabels can be incorporated into known compounds by a
number of methods. Particularly suitable for providing radioligands
of formula (III) are those wherein a .sup.14CH.sub.3 group can be
incorporated in by reaction with .sup.14CH.sub.3I. The
incorporation of .sup.14CH.sub.3I can be carried out according to a
method such as that described in Step 3 above, substituting
.sup.14CH.sub.3I for a .sup.12C.sup.3H.sub.3I. For example, as
shown below: ##STR12## wherein l, m, n, p, q, A.sub.III, and B are
as defined above for compounds of formula (III). Methods of
incorporating radiolabels into known compounds are well known to
those skilled in the art of synthetic organic chemistry or
medicinal chemistry.
[0435] Specific embodiments of radiolabelled compounds of formula
(III) include, but are not limited to, the following: [0436]
[.sup.3H]-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane, iodide (DPPB); [0437]
[.sup.3H]-(R,R)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane, iodide; [0438]
[.sup.3H]-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4--
c]pyrrol-2-ium, iodide; [0439]
[.sup.3H]-(1R,6S)-9,9-dimethyl-3-(6-phenyl-pyridazin-3-yl)-3-aza-9-azonia-
-bicyclo[4.2.1]nonane, iodide; and [0440]
[.sup.3H]-(1S,6R)-9,9-dimethyl-3-(6-phenyl-pyridazin-3-yl)-3-aza-9-azonia-
-bicyclo[4.2.1]nonane, iodide. [0441]
[.sup.3H]-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane, iodide is preferred.
[0442] 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]-DPPB, D' is
greater than about 50.
[0443] Compounds of the invention are .alpha.7 nAChRs ligands that
modulate function of .alpha.7 nAChRs by altering the activity of
the receptor or signaling. The compounds can be inverse agonists
that inhibit the basal activity of the receptor or antagonists that
completely block the action of receptor-activating agonists. The
compounds also can be partial agonists that partially block or
partially activate the .alpha.7 nAChR receptor or agonists that
activate the receptor. Binding to .alpha.7 receptor also trigger
key signaling processes involving various kinases and phosphatases
and protein-protein interactions that are important to effects on
memory, cytoprotection, gene transcription and disease
modification.
[0444] 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.
* * * * *