U.S. patent application number 12/694952 was filed with the patent office on 2010-05-27 for novel diazabicyclic aryl derivatives.
This patent application is currently assigned to NeuroSearch A/S. Invention is credited to Philip K. Ahring, Tino Dyhring Jorgensen, Elsebet Otergaard Nielsen, Gunnar M. Olsen, Dan PETERS.
Application Number | 20100130483 12/694952 |
Document ID | / |
Family ID | 32931427 |
Filed Date | 2010-05-27 |
United States Patent
Application |
20100130483 |
Kind Code |
A1 |
PETERS; Dan ; et
al. |
May 27, 2010 |
NOVEL DIAZABICYCLIC ARYL DERIVATIVES
Abstract
This invention relates to novel diazabicyclic aryl derivatives
which are found to be cholinergic ligands at the nicotinic
acetylcholine receptors. Due to their pharmacological profile the
compounds of the invention may be useful for the treatment of
diseases or disorders as diverse as those related to the
cholinergic system of the central nervous system (CNS), the
peripheral nervous system (PNS), diseases or disorders related to
smooth muscle contraction, endocrine diseases or disorders,
diseases or disorders related to neuro-degeneration, diseases or
disorders related to inflammation, pain, and withdrawal symptoms
caused by the termination of abuse of chemical substances.
Inventors: |
PETERS; Dan; (Malmoe,
SE) ; Olsen; Gunnar M.; (Ballerup, DK) ;
Nielsen; Elsebet Otergaard; (Ballerup, DK) ;
Jorgensen; Tino Dyhring; (Ballerup, DK) ; Ahring;
Philip K.; (Ballerup, DK) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
NeuroSearch A/S
Ballerup
DK
|
Family ID: |
32931427 |
Appl. No.: |
12/694952 |
Filed: |
January 27, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10547157 |
Aug 26, 2005 |
7678788 |
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PCT/EP2004/050079 |
Feb 4, 2004 |
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12694952 |
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60449871 |
Feb 27, 2003 |
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60482022 |
Jun 25, 2003 |
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Current U.S.
Class: |
514/221 ;
540/556 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 25/24 20180101; A61P 25/04 20180101; A61P 25/14 20180101; A61P
15/06 20180101; A61P 25/18 20180101; A61P 9/06 20180101; A61P 25/36
20180101; A61P 17/00 20180101; A61P 3/04 20180101; A61P 5/18
20180101; A61P 25/16 20180101; A61P 9/12 20180101; A61P 25/34
20180101; A61P 15/00 20180101; A61P 1/14 20180101; A61P 25/20
20180101; A61P 25/08 20180101; A61P 35/00 20180101; A61P 43/00
20180101; A61P 21/04 20180101; A61P 25/32 20180101; A61P 25/00
20180101; A61P 21/02 20180101; A61P 1/12 20180101; A61P 9/10
20180101; A61P 11/06 20180101; A61P 5/00 20180101; A61P 1/00
20180101; A61P 25/22 20180101; A61P 15/10 20180101; A61P 21/00
20180101; C07D 471/08 20130101 |
Class at
Publication: |
514/221 ;
540/556 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 243/10 20060101 C07D243/10; A61P 25/00 20060101
A61P025/00; A61P 25/28 20060101 A61P025/28; A61P 25/24 20060101
A61P025/24; A61P 25/18 20060101 A61P025/18; A61P 25/16 20060101
A61P025/16; A61P 3/04 20060101 A61P003/04; A61P 21/00 20060101
A61P021/00; A61P 9/10 20060101 A61P009/10; A61P 1/12 20060101
A61P001/12; A61P 11/06 20060101 A61P011/06; A61P 15/06 20060101
A61P015/06; A61P 15/00 20060101 A61P015/00; A61P 5/00 20060101
A61P005/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 27, 2003 |
DK |
PA 2003 00310 |
Jun 24, 2003 |
DK |
PA 2003 00940 |
Claims
1. A diazabicyclic aryl derivative represented by Formula I
##STR00008## any of its enantiomers or any mixture of its
enantiomers, or a prodrug, or a pharmaceutically-acceptable
addition salt thereof, wherein n is 1, 2 or 3; and X and Y,
independently of one another, represents CR.sup.2, CR.sup.3 and/or
N, wherein R.sup.2 and R.sup.3, independently of one another,
represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy,
alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy,
cyano, amino, nitro, aryl, aryloxy, aryl-alkyl, heteroaryl and/or
heteroaryloxy, which aryl, aryloxy, aryl-alkyl, heteroaryl and
heteroaryloxy may optionally be substituted one or two times with
halo, haloalkyl, haloalkoxy, cyano, amino, nitro and/or a group of
the formula R'CONH--, wherein R' represents hydrogen or alkyl; and
R.sup.1 represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,
hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, aryl or heteroaryl, which aryl or
heteroaryl may optionally be substituted one or two times with
alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro
and/or a group of the formula R'CONH--, R'SO.sub.2NH-- or
(R'SO.sub.2).sub.2N--, wherein R' represents hydrogen, alkyl,
cycloalkyl, haloalkyl, alkenyl, phenyl or benzyl; or a group of
formula aryl-alkyl-, aryl-Z-(alkyl).sub.m-, aryl-C.ident.C--,
heteroaryl-Z-(alkyl).sub.m- or heteroaryl-C.ident.C--, wherein m is
0 or 1; and Z represents O or S; and wherein the aryl and
heteroaryl may optionally be substituted one or two times with
alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino,
nitro and/or a group of the formula R'CONH--, R'SO.sub.2NH-- or
(R'SO.sub.2).sub.2N--, wherein R' represents hydrogen or alkyl; or
R.sup.1 and R.sup.2, or R.sup.1 and R.sup.3, together with the
carbon atoms to which they are bound, form a benzo-fused aromatic
carbocyclic ring, which benzo-fused aromatic carbocyclic ring may
optionally be substituted one or two times with alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro and/or a group of the
formula R'CONH--, wherein R' represents hydrogen or alkyl.
2. The diazabicyclic aryl of claim 1, wherein n is 1, 2 or 3.
3. The diazabicyclic aryl derivative of claim 1, wherein aryl is
selected from the group consisting of phenyl, indenyl and naphthyl;
and heteroaryl represents an aromatic 5- and 6-membered monocyclic
heterocyclic group selected from the group consisting of furanyl,
in particular furan-2- or 3-yl; thienyl, in particular thien-2- or
3-yl; pyrrolyl (azolyl), in particular pyrrol-2- or 3-yl; oxazolyl,
in particular oxazol-2-, 4- or 5-yl; imidazolyl, in particular
imidazol-2- or 4-yl; pyrazolyl, in particular pyrazol-1-, 3- or
4-yl; isoxazolyl, in particular isoxazol-3-, 4- or 5-yl; thiazolyl,
in particular thiazol-2-, 4- or 5-yl, thiadiazolyl, in particular
1,3,4-thiadiazol-2-yl, pyridyl, in particular pyrid-2-, 3- or 4-yl;
pyridazinyl, in particular pyridazin-3- or 4-yl; pyrimidinyl, in
particular pyrimidin-2-, 4- or 5-yl; and pyrazinyl, in particular
pyrazin-2- or 3-yl; or an aromatic bicyclic heterocyclic group the
group consisting of indolyl, in particular indol-2-, 3-, 5- or
6-yl, benzo[b]furanyl, in particular benzofuran-2-, 5- or 6-yl;
benzo[b]thienyl, in particular benzothien-2-, 5- or 6-yl;
benzoimidazolyl, in particular benzoimidazol-2-, 5- or 6-yl;
quinolinyl, in particular quinolin-2-, 3-, 6- or 7-yl;
isoquinolinyl, in particular isoquinolin-3-, 6- or 7-yl; and
cinnolinyl, in particular cinnolin-6- or 7-yl.
4. The diazabicyclic aryl derivative of claim 1, wherein aryl
represents phenyl; aryl-alkyl represents benzyl; and heteroaryl
represents furanyl, in particular furan-2- or 3-yl; imidazolyl, in
particular imidazol-2- or 4-yl; isoxazolyl, in particular
isoxazol-3-, 4- or 5-yl; thiazolyl, in particular thiazol-2-, 4- or
5-yl, thiadiazolyl, in particular 1,3,4-thiadiazol-2-yl, pyridyl,
in particular pyrid-2-, 3- or 4-yl; or indolyl, in particular
indol-2-, 3-, 5- or 6-yl.
5. The diazabicyclic aryl derivative of claim 1, wherein at least
one of X and Y represents N; and the other of X and Y represent
CR.sup.2; and n, R.sup.1 and R.sup.2 are as defined in claim 1.
6. The diazabicyclic aryl derivative of claim 5, which is
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-oxazolyl-5-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(5-phenyl-oxazol-5-yl)-methanone;
or
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenyl-1,3,4-oxadiazol-2-yl-methanon-
e; an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
7. The diazabicyclic aryl derivative of claim 1, wherein one or two
of R.sup.2 and R.sup.3, independently of one another, represent
hydrogen and/or halo; and R.sup.1 and the remainder of R.sup.2 and
R.sup.3, independently of one another, represent hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halo, CF.sub.3,
OCF.sub.3, CN, nitro, phenyl, 2-nitro-phenyl,
2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl,
3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,
2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl,
2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl,
2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl,
2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl,
N-3-phenyl-acetamide, N-4-phenyl-acetamide,
N-4-phenyl-propionamide, N-4-phenyl-isobutyramide,
N-4-phenyl-acrylamide, N-4-phenyl-benzamide,
4-(N,N-dimethyl-sulfonyl-amino)-phenyl,
N-4-phenyl-2,2,2-trifluoro-acetamide trifluoro acetic acid,
4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy,
3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyridyl-thiomethyl and/or
5-trifluoromethyl-2-pyridyl-thiomethyl.
8. The diazabicyclic aryl derivative of claim 1, wherein both of X
and Y represent CR.sup.2, CR.sup.3 or N, wherein R.sup.2 and
R.sup.3, independently of one another, represent hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl,
aryloxy, heteroaryl and/or heteroaryloxy, which aryl, aryloxy,
heteroaryl and heteroaryloxy may optionally be substituted one or
two times with halo, haloalkyl, haloalkoxy, cyano, amino, nitro
and/or a group of the formula R'CONH--, wherein R' represents
hydrogen or alkyl; or X represents N or CR.sup.2, wherein R.sup.2
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy,
alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy,
cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy,
which aryl, aryloxy, heteroaryl or heteroaryloxy may optionally be
substituted one or two times with halo, haloalkyl, haloalkoxy,
cyano, amino, nitro and/or a group of the formula R'CONH--, wherein
R' represents hydrogen or alkyl; and Y represents N or CR.sup.3,
wherein R.sup.3 together with R', and together with the carbon
atoms to which they are bound, form a benzo-fused aromatic
carbocyclic ring, which benzo-fused aromatic carbocyclic ring may
optionally be substituted one or two times with alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro and/or a group of the
formula R'CONH--, wherein R' represents hydrogen or alkyl.
9. The diazabicyclic aryl derivative of claim 1, represented by
Formula II ##STR00009## any of its enantiomers or any mixture of
its enantiomers, or a prodrug, or a pharmaceutically-acceptable
addition salt thereof, wherein n is 1, 2 or 3; and X represents
CR.sup.4 or N, wherein R.sup.4 represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl,
aryloxy, heteroaryl or heteroaryloxy, which aryl, aryloxy,
heteroaryl or heteroaryloxy may optionally be substituted one or
two times with halo, haloalkyl, haloalkoxy, cyano, amino, nitro
and/or a group of the formula R'CONH--, wherein R' represents
hydrogen or alkyl; R.sup.1 and R.sup.2, independently of each
other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,
hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, phenyl, phenyloxy, heteroaryl
and/or heteroaryloxy, which phenyl, phenyloxy, heteroaryl and
heteroaryloxy may optionally be substituted one or two times with
alkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, a group of
the formula R'CONH--, R'SO.sub.2NH-- and/or (R'SO.sub.2).sub.2N--,
wherein R' represents hydrogen, alkyl, cycloalkyl, haloalkyl,
alkenyl, phenyl or benzyl; wherein R' represents hydrogen or alkyl;
or R.sup.1 and R.sup.2, together with the carbon atoms to which
they are bound, form a benzo-fused aromatic benzene ring, which
benzene ring may optionally be substituted one or two times with
alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl,
aryloxy, heteroaryl or heteroaryloxy, which aryl, aryloxy,
heteroaryl or heteroaryloxy may optionally be substituted one or
two times with halo, haloalkyl, haloalkoxy, cyano, amino, nitro
and/or a group of the formula R' CONH--, wherein R' represents
hydrogen or alkyl.
10. The diazabicyclic aryl derivative of claim 9, wherein R.sup.1
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, CN, nitro, phenyl, 2-nitro-phenyl,
2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl,
3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,
2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl,
2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl,
2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl,
2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl,
N-3-phenyl-acetamide, N-4-phenyl-acetamide,
N-4-phenyl-propionamide, N-4-phenyl-isobutyramide,
N-4-phenyl-acrylamide, N-4-phenyl-benzamide,
4-(N,N-dimethyl-sulfonyl-amino)-phenyl,
N-4-phenyl-2,2,2-trifluoro-acetamide trifluoro acetic acid,
4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy,
3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyridyl-thiomethyl or
5-trifluoromethyl-2-pyridyl-thiomethyl; R.sup.2 represents hydrogen
or halo; and R.sup.4 represents hydrogen, alkyl or halo.
11. The diazabicyclic aryl derivative of claim 1, represented by
Formula III ##STR00010## any of its enantiomers or any mixture of
its enantiomers, or a prodrug, or a pharmaceutically-acceptable
addition salt thereof, wherein n is 1, 2 or 3; and X represents
CR.sup.4 or N, wherein R.sup.4 represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl,
aryloxy, heteroaryl or heteroaryloxy; R.sup.5 and R.sup.6,
independently of each other, represent hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy,
heteroaryl or heteroaryloxy.
12. The diazabicyclic aryl derivative of claim 11, wherein R.sup.4
represents hydrogen or alkyl; R.sup.5 represents hydrogen, alkyl or
alkoxy; and R.sup.6 represents hydrogen, alkyl or alkoxy.
13. The diazabicyclic aryl derivative of claim 11, which is
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-8-methoxy-benzofuran-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzofuran-2-yl-methanone; or
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-benzofuran-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzooxazol-2-yl-methanone; an
enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
14. The diazabicyclic aryl derivative of claim 1, wherein R.sup.1
represents a group of formula -(alkyl).sub.m-Z-aryl,
-(alkyl).sub.m-Z-heteroaryl or --C.ident.C-aryl, wherein m is 0 or
1; and Z represents O or S; and wherein the aryl and heteroaryl may
optionally be substituted one or two times with alkyl, halo,
haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and/or a group
of the formula R'CONH--, R'SO.sub.2NH-- or (R'SO.sub.2).sub.2N--,
wherein R' represents hydrogen or alkyl.
15. The diazabicyclic aryl derivative of claim 14, wherein R.sup.1
represents a group of formula --CH.sub.2-Z-phenyl,
--CH.sub.2-Z-pyridyl or --C.ident.C-phenyl, wherein m is 0 or 1;
and Z represents O or S; and wherein the phenyl and pyridyl group
may optionally be substituted one or two times with alkyl, halo,
haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and/or a group
of the formula R'CONH--, R'SO.sub.2NH-- or (R'SO.sub.2).sub.2N--,
wherein R' represents hydrogen or alkyl.
16. The diazabicyclic aryl derivative of claim 15, which is
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-met-
hanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl-
)-thiomethyl]-furan-2-yl-methanone; or
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanone;
an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
17. The diazabicyclic aryl of claim 1, wherein n is 2.
18. The diazabicyclic aryl derivative of claim 1, wherein R.sup.1
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, CN, nitro, phenyl, 2-nitro-phenyl,
2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl,
3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,
2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl,
2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl,
2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl,
2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl,
N-3-phenyl-acetamide, N-4-phenyl-acetamide,
N-4-phenyl-propionamide, N-4-phenyl-isobutyramide,
N-4-phenyl-acrylamide, N-4-phenyl-benzamide,
4-(N,N-dimethyl-sulfonyl-amino)-phenyl,
N-4-phenyl-2,2,2-trifluoro-acetamide trifluoro acetic acid,
4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy,
3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyridyl-thiomethyl or
5-trifluoromethyl-2-pyridyl-thiomethyl; R.sup.2 represents
hydrogen, alkyl or halo; and R.sup.3 represents hydrogen, alkyl or
halo.
19. The diazabicyclic aryl derivative of claim 18, which is
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-bromo-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-nitro-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(5-phenyl-furan-2-yl)-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone-
;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-trifluoromethylphenyl)-furan-2-y-
l-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone-
;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-chlorophenyl)-furan-2-yl-methano-
ne;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methan-
one;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-metha-
none;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-acetylaminophenyl)-furan-2-y-
l-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-aminophenyl)-furan-2-yl-methanone-
;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-aminophenyl)-furan-2-yl-methanon-
e;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-acetylaminophenyl)-furan-2-yl-m-
ethanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-acetylaminophenyl)-furan-
-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-4,5-dibromo-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-chloro-5-trifluoromethylphenyl)-f-
uran-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-methylphenyl)-furan-2-yl--
methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-amino-4-methylphenyl)-f-
uran-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-dimethylsulfonyl)aminophenyl-
]-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-formylaminophenyl)-furan-2-yl-met-
hanone;
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-ph-
enyl}-propionamide;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-met-
hanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl-
)-thiomethyl]-furan-2-yl-methanone;
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-2-
,2,2-trifluoro-acetamide trifluoro acetic acid;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-bromo-furan-2-yl-methanone;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanone;
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-a-
crylamide;
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-
-phenyl}-benzamide;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-diphenylsulfonylamino)phenyl-
]-furan-2-yl-methanone;
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-i-
sobutyramide; Cyclopropanecarboxylic acid
{4-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-ami-
de;
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methan-
one;
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-pheny-
l}-acrylamide N-oxide; or
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-a-
crylamide; an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
20. A pharmaceutical composition comprising a therapeutically
effective amount of a diazabicyclic aryl derivative of claim 1, or
a pharmaceutically-acceptable addition salt thereof, together with
at least one pharmaceutically-acceptable carrier or diluent.
21. A method of treatment, prevention or alleviation of a disease
or a disorder or a condition of a living animal body, including a
human, which disorder, disease or condition is responsive to
modulation of cholinergic receptors, which method comprises the
step of administering to such a living animal body in need thereof
a therapeutically effective amount of a diazabicyclic aryl
derivative of any one of claim 1.
22. The method according to claim 21, wherein the disease, disorder
or condition relates to the central nervous system.
23. The method according to claim 22, wherein the disease, disorder
or condition is anxiety, cognitive disorders, learning deficit,
memory deficits and dysfunction, Alzheimer's disease, attention
deficit, attention deficit hyperactivity disorder, Parkinson's
disease, Huntington's disease, Amyotrophic Lateral Sclerosis,
Gilles de la Tourette's syndrome, depression, mania, manic
depression, schizophrenia, obsessive compulsive disorders (OCD),
panic disorders, eating disorders such as anorexia nervosa, bulimia
and obesity, narcolepsy, nociception, AIDS-dementia, senile
dementia, periferic neuropathy, autism, dyslexia, tardive
dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic
syndrome, social phobia, sleeping disorders, pseudodementia,
Ganser's syndrome, pre-menstrual syndrome, late luteal phase
syndrome, chronic fatigue syndrome, mutism, trichotillomania and
jet-lag.
24. The method according to claim 21, wherein the disease, disorder
or condition are associated with smooth muscle contractions,
including convulsive disorders, angina pectoris, premature labour,
convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia,
hyperkinesia, premature ejaculation and erectile difficulty.
25. The method according to claim 21, wherein the disease, disorder
or condition is related to the endocrine system, such as
thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
26. The method according to claim 21, wherein the disease, disorder
or condition is a neurodegenerative disorders, including transient
anoxia and induced neuro-degeneration.
27. The method according to claim 21, wherein the disease, disorder
or condition is an inflammatory disorder, including inflammatory
skin disorders such as acne and rosacea, Chron's disease,
inflammatory bowel disease, ulcerative colitis and diarrhea.
28. The method according to claim 21, wherein the disease, disorder
or condition is mild, moderate or even severe pain of acute,
chronic or recurrent character, as well as neuropathic pain and
pain caused by migraine, postoperative pain, phantom limb pain,
neuropathic pain, chronic headache, central pain, pain related to
diabetic neuropathy, to post therapeutic neuralgia, or to
peripheral nerve injury.
29. The method according to claim 21, wherein the disease, disorder
or condition is associated with withdrawal symptoms caused by
termination of use of addictive substances, including nicotine
containing products such as tobacco, opioids such as heroin,
cocaine and morphine, benzodiazepines and benzodiazepine-like drugs
and alcohol.
30. (canceled)
Description
TECHNICAL FIELD
[0001] This invention relates to novel diazabicyclic aryl
derivatives, which are found to be cholinergic ligands at the
nicotinic acetylcholine receptors. Due to their pharmacological
profile the compounds of the invention may be useful for the
treatment of diseases or disorders as diverse as those related to
the cholinergic system of the central nervous system (CNS), the
peripheral nervous system (PNS), diseases or disorders related to
smooth muscle contraction, endocrine diseases or disorders,
diseases or disorders related to neuro-degeneration, diseases or
disorders related to inflammation, pain, and withdrawal symptoms
caused by the termination of abuse of chemical substances.
BACKGROUND ART
[0002] The endogenous cholinergic neurotransmitter, acetylcholine,
exert its biological effect via two types of cholinergic receptors,
the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic
Acetyl Choline Receptors (nAChR). As it is well established that
muscarinic acetylcholine receptors dominate quantitatively over
nicotinic acetylcholine receptors in the brain area important to
memory and cognition, and much research aimed at the development of
agents for the treatment of memory related disorders have focused
on the synthesis of muscarinic acetylcholine receptor
modulators.
[0003] Recently, however, an interest in the development of nAChR
modulators has emerged. Several diseases are associated with
degeneration of the cholinergic system i.e. senile dementia of the
Alzheimer type, vascular dementia and cognitive impairment due to
the organic brain damage disease related directly to
alcoholism.
[0004] WO 00/58311 discloses
1,4-diazabicyclo[3.2.2]nonane-4-carboxylates and carboxamide
derivatives useful as inhibitors of the nicotinic .alpha.7 receptor
subtype. Other 1,4-diazabicyclo[3.2.2]nonane-4-methanone
derivatives are not disclosed.
SUMMARY OF THE INVENTION
[0005] The present invention is devoted to the provision novel
modulators of the nicotinic receptors, which modulators are useful
for the treatment of diseases or disorders related to the
cholinergic receptors, and in particular the nicotinic
acetylcholine .alpha.7 receptor subtype.
[0006] The compounds of the invention may also be useful as
diagnostic tools or monitoring agents in various diagnostic
methods, and in particular for in vivo receptor imaging
(neuroimaging), and they may be used in labelled or unlabelled
form.
[0007] In its first aspect the invention provides diazabicyclic
aryl derivatives of Formula I
##STR00001##
[0008] any of its enantiomers or any mixture of its enantiomers, or
a prodrug, or a pharmaceutically-acceptable addition salt thereof,
wherein
[0009] n is 1, 2 or 3; and
[0010] X and Y, independently of one another, represents CR.sup.2,
CR.sup.3 and/or N, wherein R.sup.2 and R.sup.3, independently of
one another, represent hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy,
aryl-alkyl, heteroaryl and/or heteroaryloxy, which aryl, aryloxy,
aryl-alkyl, heteroaryl and heteroaryloxy may optionally be
substituted one or two times with halo, haloalkyl, haloalkoxy,
cyano, amino, nitro and/or a group of the formula R'CONH--, wherein
R' represents hydrogen or alkyl; and
[0011] R.sup.1 represents hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro, aryl or heteroaryl,
which aryl or heteroaryl may optionally be substituted one or two
times with alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano,
amino, nitro and/or a group of the formula R'CONH--, R'SO.sub.2NH--
or (R'SO.sub.2).sub.2N--, wherein R' represents hydrogen, alkyl,
cycloalkyl, haloalkyl, alkenyl, phenyl or benzyl; or a group of
formula aryl-alkyl-, aryl-Z-(alkyl).sub.m-, aryl-C
heteroaryl-Z-(alkyl).sub.m- or heteroaryl-C wherein m is 0 or 1;
and Z represents O or S; and wherein the aryl and heteroaryl may
optionally be substituted one or two times with alkyl, halo,
haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, nitro and/or
a group of the formula R'CONH--, R'SO.sub.2NH-- or
(R'SO.sub.2).sub.2N--, wherein R' represents hydrogen or alkyl;
or
[0012] R.sup.1 and R.sup.2, or R.sup.1 and R.sup.3, together with
the carbon atoms to which they are bound, form a benzo-fused
aromatic carbocyclic ring, which benzo-fused aromatic carbocyclic
ring may optionally be substituted one or two times with alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro and/or
a group of the formula R'CONH--, wherein R' represents hydrogen or
alkyl.
[0013] In a second aspect the invention provides pharmaceutical
compositions comprising a therapeutically effective amount of the
diazabicyclic aryl derivative of the invention, or a
pharmaceutically-acceptable addition salt thereof, together with at
least one pharmaceutically-acceptable carrier or diluent.
[0014] Viewed from another aspect the invention relates to the use
of the diazabicyclic aryl derivative of the invention, or a
pharmaceutically-acceptable addition salt thereof, for the
manufacture of pharmaceutical compositions/medicaments for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a mammal, including a human, which disease, disorder
or condition is responsive to modulation of cholinergic
receptors.
[0015] In yet another aspect the invention provides a method for
treatment, prevention or alleviation of diseases, disorders or
conditions of a living animal body, including a human, which
disorder, disease or condition is responsive to modulation of
cholinergic receptors, and which method comprises the step of
administering to such a living animal body in need thereof a
therapeutically effective amount of the diazabicyclic aryl
derivative of the invention.
[0016] Other objects of the invention will be apparent to the
person skilled in the art from the following detailed description
and examples.
DETAILED DISCLOSURE OF THE INVENTION
Diazabicyclic Aryl Derivatives
[0017] In a first aspect the invention provides a diazabicyclic
aryl derivative of Formula I
##STR00002##
[0018] any of its enantiomers or any mixture of its enantiomers, or
a prodrug, or a pharmaceutically-acceptable addition salt thereof,
wherein
[0019] n is 1, 2 or 3; and
[0020] X and Y, independently of one another, represents CR.sup.2,
CR.sup.3 and/or N, wherein R.sup.2 and R.sup.3, independently of
one another, represent hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy,
aryl-alkyl, heteroaryl and/or heteroaryloxy, which aryl, aryloxy,
aryl-alkyl, heteroaryl and heteroaryloxy may optionally be
substituted one or two times with halo, haloalkyl, haloalkoxy,
cyano, amino, nitro and/or a group of the formula R'CONH--, wherein
R' represents hydrogen or alkyl; and
[0021] R.sup.1 represents hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro, aryl or heteroaryl,
which aryl or heteroaryl may optionally be substituted one or two
times with alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano,
amino, nitro and/or a group of the formula R'CONH--, R'SO.sub.2NH--
or (R'SO.sub.2).sub.2N--, wherein R' represents hydrogen, alkyl,
cycloalkyl, haloalkyl, alkenyl, phenyl or benzyl; or a group of
formula aryl-alkyl-, aryl-Z-(alkyl).sub.m-, aryl-C
heteroaryl-Z-(alkyl).sub.m- or heteroaryl-C wherein m is 0 or 1;
and Z represents O or S; and wherein the aryl and heteroaryl may
optionally be substituted one or two times with alkyl, halo,
haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, nitro and/or
a group of the formula R'CONH--, R'SO.sub.2NH-- or
(R'SO.sub.2).sub.2N--, wherein R' represents hydrogen or alkyl;
or
[0022] R.sup.1 and R.sup.2, or R.sup.1 and R.sup.3, together with
the carbon atoms to which they are bound, form a benzo-fused
aromatic carbocyclic ring, which benzo-fused aromatic carbocyclic
ring may optionally be substituted one or two times with alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro and/or
a group of the formula R'CONH--, wherein R' represents hydrogen or
alkyl.
[0023] In a preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, wherein
[0024] X represents CR.sup.3 or N, wherein R.sup.3 represents
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkoxy,
cyanoalkyl, halogen, CF.sub.3, OCF.sub.3, CN, amino, nitro, aryl,
aryloxy, heteroaryl or heteroaryloxy;
[0025] R.sup.1 and R.sup.2, independently of each other, represent
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkoxy,
cyanoalkyl, halogen, CF.sub.3, OCF.sub.3, CN, amino, nitro, aryl,
aryloxy, heteroaryl or heteroaryloxy; or
[0026] R.sup.1 and R.sup.2, together with the carbon atoms to which
they are bound, form a benzo-fused aromatic carbocyclic ring.
[0027] In another preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, wherein
[0028] X and Y, independently of one another, represents CR.sup.2
or N, wherein R.sup.2 represents hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or
heteroaryloxy, which aryl, aryloxy, heteroaryl or heteroaryloxy may
optionally be substituted one or two times with halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, and/or a group of the formula
R'CONH--, wherein R' represents hydrogen or alkyl; and
[0029] R.sup.1 represent hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or
heteroaryloxy, which aryl, aryloxy, heteroaryl or heteroaryloxy may
optionally be substituted one or two times with halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, and/or a group of the formula
R'CONH--, wherein R' represents hydrogen or alkyl; or
[0030] R.sup.1 and R.sup.2, together with the carbon atoms to which
they are bound, form a benzo-fused aromatic carbocyclic ring, which
benzo-fused aromatic carbocyclic ring may optionally be substituted
one or two times with alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino,
nitro, and/or a group of the formula R'CONH--, wherein R'
represents hydrogen or alkyl.
[0031] In a more preferred embodiment aryl is selected from the
group consisting of phenyl, indenyl and naphthyl; and
[0032] heteroaryl represents an aromatic 5- and 6-membered
monocyclic heterocyclic group selected from the group consisting of
furanyl, in particular furan-2- or 3-yl; thienyl, in particular
thien-2- or 3-yl; pyrrolyl (azolyl), in particular pyrrol-2- or
3-yl; oxazolyl, in particular oxazol-2-, 4- or 5-yl; imidazolyl, in
particular imidazol-2- or 4-yl; pyrazolyl, in particular
pyrazol-1-, 3- or 4-yl; isoxazolyl, in particular isoxazol-3-, 4-
or 5-yl; thiazolyl, in particular thiazol-2-, 4- or 5-yl,
thiadiazolyl, in particular 1,3,4-thiadiazol-2-yl, pyridyl, in
particular pyrid-2-, 3- or 4-yl; pyridazinyl, in particular
pyridazin-3- or 4-yl; pyrimidinyl, in particular pyrimidin-2-, 4-
or 5-yl; and pyrazinyl, in particular pyrazin-2- or 3-yl; or an
aromatic bicyclic heterocyclic group the group consisting of
indolyl, in particular indol-2-, 3-, 5- or 6-yl, benzo[b]furanyl,
in particular benzofuran-2-, 5- or 6-yl; benzo[b]thienyl, in
particular benzothien-2-, 5- or 6-yl; benzoimidazolyl, in
particular benzoimidazol-2-, 5- or 6-yl; quinolinyl, in particular
quinolin-2-, 3-, 6- or 7-yl; isoquinolinyl, in particular
isoquinolin-3-, 6- or 7-yl; and cinnolinyl, in particular
cinnolin-6- or 7-yl.
[0033] In a even more preferred embodiment aryl represents phenyl;
aryl-alkyl represents benzyl; and heteroaryl represents furanyl, in
particular furan-2- or 3-yl; imidazolyl, in particular imidazol-2-
or 4-yl; isoxazolyl, in particular isoxazol-3-, 4- or 5-yl;
thiazolyl, in particular thiazol-2-, 4- or 5-yl, thiadiazolyl, in
particular 1,3,4-thiadiazol-2-yl, pyridyl, in particular pyrid-2-,
3- or 4-yl; or indolyl, in particular indol-2-, 3-, 5- or 6-yl.
[0034] In a third preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, 1a, 1b, II or III,
wherein n is 1, 2 or 3. In a more preferred embodiment the
diazabicyclic aryl of the invention is a diazabicyclic aryl
derivative of Formula I, 1a, 1b, II or III, wherein n is 2.
[0035] In a fourth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, wherein at least one of
X and Y represents N; and the other of X and Y represent CR.sup.2;
and n, R.sup.1 and R.sup.2 are as defined above.
[0036] In a fifth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula Ia or Ib,
##STR00003##
[0037] wherein, n and R.sup.1 are as defined above.
[0038] In a sixth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula Ic or Id,
##STR00004##
[0039] wherein, R.sup.1 is as defined above.
[0040] In a most preferred embodiment the diazabicyclic aryl
derivative of the invention is [0041]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-oxazolyl-5-yl-methanone; [0042]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(5-phenyl-oxazol-5-yl)-methanone;
or [0043]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenyl-1,3,4-oxadiazol-2-yl-m-
ethanone;
[0044] an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
[0045] In a seventh preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, wherein one or two of
R.sup.2 and R.sup.3, independently of one another, represent
hydrogen and/or halo; and R.sup.1 and the remainder of R.sup.2 and
R.sup.3, independently of one another, represent hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halo, CF.sub.3,
OCF.sub.3, CN, nitro, phenyl, 2-nitro-phenyl,
2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl,
3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,
2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl,
2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl,
2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl,
2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl,
N-3-phenyl-acetamide, N-4-phenyl-acetamide,
N-4-phenyl-propionamide, N-4-phenyl-isobutyramide,
N-4-phenyl-acrylamide, N-4-phenyl-benzamide,
4-(N,N-dimethyl-sulfonyl-amino)-phenyl,
N-4-phenyl-2,2,2-trifluoro-acetamide trifluoro acetic acid,
4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy,
3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyridyl-thiomethyl and/or
5-trifluoromethyl-2-pyridyl-thiomethyl.
[0046] In an eighth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, wherein one of R.sup.1
and R.sup.2 represents phenyl or naphthyl; and the other of R.sup.1
and R.sup.2 represents hydrogen.
[0047] In a ninth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, wherein both of X and Y
represent CR.sup.2, CR.sup.3 or N, wherein R.sup.2 and R.sup.3,
independently of one another, represent hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl,
aryloxy, heteroaryl and/or heteroaryloxy, which aryl, aryloxy,
heteroaryl and heteroaryloxy may optionally be substituted one or
two times with halo, haloalkyl, haloalkoxy, cyano, amino, nitro
and/or a group of the formula R'CONH--, wherein R' represents
hydrogen or alkyl; or X represents N or CR.sup.2, wherein R.sup.2
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy,
alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy,
cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy,
which aryl, aryloxy, heteroaryl or heteroaryloxy may optionally be
substituted one or two times with halo, haloalkyl, haloalkoxy,
cyano, amino, nitro and/or a group of the formula R'CONH--, wherein
R' represents hydrogen or alkyl; and Y represents N or CR.sup.3,
wherein R.sup.3 together with R.sup.1, and together with the carbon
atoms to which they are bound, form a benzo-fused aromatic
carbocyclic ring, which benzo-fused aromatic carbocyclic ring may
optionally be substituted one or two times with alkyl, cycloalkyl,
cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo,
haloalkyl, haloalkoxy, cyano, amino, nitro and/or a group of the
formula R'CONH--, wherein R' represents hydrogen or alkyl.
[0048] In a tenth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula II,
##STR00005##
[0049] any of its enantiomers or any mixture of its enantiomers, or
a prodrug, or a pharmaceutically-acceptable addition salt thereof,
wherein
[0050] n is 1, 2 or 3; and
[0051] X represents CR.sup.4 or N, wherein R.sup.4 represents
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy,
cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino,
nitro, aryl, aryloxy, heteroaryl or heteroaryloxy, which aryl,
aryloxy, heteroaryl or heteroaryloxy may optionally be substituted
one or two times with halo, haloalkyl, haloalkoxy, cyano, amino,
nitro and/or a group of the formula R'CONH--, wherein R' represents
hydrogen or alkyl;
[0052] R.sup.1 and R.sup.2, independently of each other, represent
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy,
cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino,
nitro, phenyl, phenyloxy, heteroaryl and/or heteroaryloxy, which
phenyl, phenyloxy, heteroaryl and heteroaryloxy may optionally be
substituted one or two times with alkyl, halo, haloalkyl,
haloalkoxy, cyano, amino, nitro, a group of the formula R'CONH--,
R'SO.sub.2NH-- and/or (R'SO.sub.2).sub.2N--, wherein R' represents
hydrogen, alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl or
benzyl;
[0053] wherein R' represents hydrogen or alkyl; or
[0054] R.sup.1 and R.sup.2, together with the carbon atoms to which
they are bound, form a benzo-fused aromatic benzene ring, which
benzene ring may optionally be substituted one or two times with
alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy,
cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl,
aryloxy, heteroaryl or heteroaryloxy, which aryl, aryloxy,
heteroaryl or heteroaryloxy may optionally be substituted one or
two times with halo, haloalkyl, haloalkoxy, cyano, amino, nitro
and/or a group of the formula R'CONH--, wherein R' represents
hydrogen or alkyl.
[0055] In a more preferred embodiment the diazabicyclic aryl
derivative of the invention is a diazabicyclic aryl derivative of
Formula II, wherein
[0056] R.sup.1 represents hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, CN, nitro,
phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl,
4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,
2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl,
2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl,
2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl,
2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl,
N-3-phenyl-acetamide, N-4-phenyl-acetamide,
N-4-phenyl-propionamide, N-4-phenyl-isobutyramide,
N-4-phenyl-acrylamide, N-4-phenyl-benzamide,
4-(N,N-dimethyl-sulfonyl-amino)-phenyl,
N-4-phenyl-2,2,2-trifluoro-acetamide trifluoro acetic acid,
4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy,
3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyridyl-thiomethyl or
5-trifluoromethyl-2-pyridyl-thiomethyl;
[0057] R.sup.2 represents hydrogen or halo; and
[0058] R.sup.4 represents hydrogen, alkyl or halo.
[0059] In an eleventh preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula III,
##STR00006##
[0060] any of its enantiomers or any mixture of its enantiomers, or
a prodrug, or a pharmaceutically-acceptable addition salt thereof,
wherein
[0061] n is 1, 2 or 3; and
[0062] X represents CR.sup.4 or N, wherein R.sup.4 represents
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy,
cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino,
nitro, aryl, aryloxy, heteroaryl or heteroaryloxy;
[0063] R.sup.5 and R.sup.6, independently of each other, represent
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy,
cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino,
nitro, aryl, aryloxy, heteroaryl or heteroaryloxy.
[0064] In a more preferred embodiment the diazabicyclic aryl
derivative of the invention is a diazabicyclic aryl derivative of
Formula III, wherein R.sup.4 represents hydrogen or alkyl; R.sup.5
represents hydrogen, alkyl or alkoxy; and R.sup.6 represents
hydrogen, alkyl or alkoxy.
[0065] In a most preferred embodiment the diazabicyclic aryl
derivative of the invention is [0066]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-8-methoxy-benzofuran-2-yl-methanone;
[0067]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzofuran-2-yl-methanone; or
[0068]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-benzofuran-2-yl-methan-
one; [0069]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzooxazol-2-yl-methanone;
[0070] an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
[0071] In a twelfth preferred embodiment the invention provides a
diazabicyclic aryl derivative of Formula I, Ia, Ib or II,
wherein
[0072] R.sup.1 represents a group of formula -(alkyl).sub.m-Z-aryl,
-(alkyl).sub.m-Z-heteroaryl or --C.ident.C-aryl, wherein m is 0 or
1; and Z represents O or S; and wherein the aryl and heteroaryl may
optionally be substituted one or two times with alkyl, halo,
haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and/or a group
of the formula R'CONH--, R'SO.sub.2NH-- or (R'SO.sub.2).sub.2N--,
wherein R' represents hydrogen or alkyl.
[0073] In a thirteenth preferred embodiment the invention provides
a diazabicyclic aryl derivative of Formula I, Ia, Ib or II, wherein
R.sup.1 represents a group of formula --CH.sub.2-Z-phenyl,
--CH.sub.2-Z-pyridyl or --C.ident.C-phenyl, wherein m is 0 or 1;
and Z represents O or S; and wherein the phenyl and pyridyl group
may optionally be substituted one or two times with alkyl, halo,
haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and/or a group
of the formula R'CONH--, R'SO.sub.2NH-- or (R'SO.sub.2).sub.2N--,
wherein R' represents hydrogen or alkyl.
[0074] In a most preferred embodiment the diazabicyclic aryl
derivative of the invention is [0075]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-met-
hanone; [0076]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiom-
ethyl]-furan-2-yl-methanone; or [0077]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanone;
[0078] an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
[0079] In a fourteenth preferred embodiment the invention provides
a diazabicyclic aryl derivative of Formula I or II, wherein R.sup.1
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, CN, nitro, phenyl, 2-nitro-phenyl,
2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl,
3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,
2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl,
2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl,
2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl,
2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl,
N-3-phenyl-acetamide, N-4-phenyl-acetamide,
N-4-phenyl-propionamide, N-4-phenyl-isobutyramide,
N-4-phenyl-acrylamide, N-4-phenyl-benzamide,
4-(N,N-dimethyl-sulfonyl-amino)-phenyl,
N-4-phenyl-2,2,2-trifluoro-acetamide trifluoro acetic acid,
4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy,
3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyridyl-thiomethyl or
5-trifluoromethyl-2-pyridyl-thiomethyl;
[0080] R.sup.2 represents hydrogen, alkyl or halo; and
[0081] R.sup.3 represents hydrogen, alkyl or halo.
[0082] In a most preferred embodiment the diazabicyclic aryl
derivative of the invention is [0083]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-furan-2-yl-methanone; [0084]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-bromo-furan-2-yl-methanone;
[0085]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-nitro-furan-2-yl-methanone;
[0086]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(5-phenyl-furan-2-yl)-methanone;
[0087]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-me-
thanone; [0088]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-trifluoromethylphenyl)-furan-2-yl-
-methanone; [0089]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone-
; [0090]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-chlorophenyl)-furan-2-yl--
methanone; [0091]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanone-
; [0092]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-m-
ethanone; [0093]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-acetylaminophenyl)-furan-2-yl-met-
hanone; [0094]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-aminophenyl)-furan-2-yl-methanone-
; [0095]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-aminophenyl)-furan-2-yl-m-
ethanone; [0096]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-acetylaminophenyl)-furan-2-yl-met-
hanone [0097]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-acetylaminophenyl)-furan-2-yl-met-
hanone; [0098]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-furan-2-yl-methanone;
[0099]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-4,5-dibromo-furan-2-yl-methanone;
[0100]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-chloro-5-trifluoromethylph-
enyl)-furan-2-yl-methanone; [0101]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-methylphenyl)-furan-2-yl--
methanone; [0102]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-amino-4-methylphenyl)-furan-2-yl--
methanone; [0103]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-dimethylsulfonyl)aminophenyl-
]-furan-2-yl-methanone; [0104]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-formylaminophenyl)-furan-2-yl-met-
hanone; [0105]
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-p-
ropionamide; [0106]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-met-
hanone; [0107]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiom-
ethyl]-furan-2-yl-methanone; [0108]
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-2-
,2,2-trifluoro-acetamide trifluoro acetic acid; [0109]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-bromo-furan-2-yl-methanone;
[0110]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanone;
[0111]
N-{-4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-p-
henyl}-acrylamide; [0112]
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-b-
enzamide; [0113]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-diphenylsulfonylamino)phenyl-
]-furan-2-yl-methanone; [0114]
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-i-
sobutyramide;
[0115] Cyclopropanecarboxylic acid
{4-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-ami-
de; [0116]
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-
-methanone; [0117]
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-a-
crylamide N-oxide; or [0118]
N-[4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl]-a-
crylamide;
[0119] an enantiomers or a mixture of its enantiomers, or a
pharmaceutically-acceptable addition salt thereof.
[0120] Any combination of two or more of the embodiments described
herein is considered within the scope of the present invention.
DEFINITION OF SUBSTITUENTS
[0121] In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contain of from one to eighteen carbon
atoms (C.sub.1-18-alkyl), more preferred of from one to six carbon
atoms (C.sub.1-6-alkyl; lower alkyl), including pentyl, isopentyl,
neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred
embodiment alkyl represents a C.sub.1-4-alkyl group, including
butyl, isobutyl, secondary butyl, and tertiary butyl. In another
preferred embodiment of this invention alkyl represents a
C.sub.1-3-alkyl group, which may in particular be methyl, ethyl,
propyl or isopropyl.
[0122] In the context of this invention a cycloalkyl group
designates a cyclic alkyl group, preferably containing of from
three to seven carbon atoms (C.sub.3-7-cycloalkyl), including
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0123] In the context of this invention a cycloalkyl-alkyl group
designates a cycloalkyl group as defined above, which cycloalkyl
group is substituted on an alkyl group as also defined above.
Examples of preferred cycloalkyl-alkyl groups of the invention
include cyclopropylmethyl and cyclopropylethyl.
[0124] In the context of this invention an alkoxy group designates
an "alkyl-O--" group, wherein alkyl is as defined above. Examples
of preferred alkoxy groups of the invention include methoxy and
ethoxy.
[0125] In the context of this invention a cycloalkoxy group
designates a "cycloalkyl-O--" group, wherein cycloalkyl is as
defined above.
[0126] In the context of this invention a cyano-alkyl group
designates an alkyl group substituted with CN, wherein alkyl is as
defined above.
[0127] In the context of this invention halo represents fluoro,
chloro, bromo or iodo, and haloalkyl group designates an alkyl
group as defined herein, which alkyl group is substituted one or
more times with halo. Thus a trihalomethyl group represents e.g. a
trifluoromethyl group, a trichloromethyl group, and similar
trihalo-substituted methyl groups. Preferred haloalkyl groups of
the invention include trihalogenmethyl, preferably CF.sub.3.
[0128] In the context of this invention a haloalkoxy group
designates an alkoxy group as defined herein, which alkoxy group is
substituted one or more times with halo. Preferred haloalkoxy
groups of the invention include trihalogenmethoxy, preferably
CF.sub.3O--.
[0129] In the context of this invention an aryl group designates a
monocyclic or polycyclic aromatic hydrocarbon group. Examples of
preferred aryl groups of the invention include phenyl, indenyl,
naphthyl, azulenyl, fluorenyl, and anthracenyl. The most preferred
aryl group of the invention is phenyl.
[0130] In the context of this invention an aryloxy group designates
an "aryl-O--" group, wherein aryl is as defined above. The most
preferred aryloxy group of the invention is phenoxy.
[0131] In the context of this invention a heteroaryl group
designates an aromatic mono- or polycyclic heterocyclic group,
which holds one or more heteroatoms in its ring structure.
Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur
(S).
[0132] Preferred 5-6 membered heteroaryl groups of the invention
include furanyl, in particular furan-2- or 3-yl; thienyl, in
particular thien-2- or 3-yl; selenophenyl, in particular
selenophen-2- or 3-yl; pyrrolyl (azolyl), in particular pyrrol-2-
or 3-yl; oxazolyl, in particular oxazol-2,4- or 5-yl; thiazolyl, in
particular thiazol-2,4- or 5-yl; imidazolyl, in particular
imidazol-2- or 4-yl; pyrazolyl, in particular pyrazol-3- or 4-yl;
isoxazolyl, in particular isoxazol-3,4- or 5-yl; isothiazolyl, in
particular isothiazol-3-, 4- or 5-yl; oxadiazolyl, in particular
1,2,3-oxadiazol-4- or 5-yl, or 1,3,4-oxadiazol-2-yl; triazolyl, in
particular 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl; thiadiazolyl,
in particular 1,2,3-thiadiazol-4- or 5-yl, or
1,3,4-thiadiazol-2-yl; pyridyl, in particular pyrid-2-, 3- or 4-yl;
pyridazinyl, in particular pyridazin-3- or 4-yl; pyrimidinyl, in
particular pyrimidin-2-, 4- or 5-yl; pyrazinyl, in particular
pyrazin-2- or 3-yl; and triazinyl, in particular 1,2,4- or
1,3,5-triazinyl.
[0133] More preferred 5 membered heteroaryl groups of the invention
include furanyl, in particular furan-2- or 3-yl; thienyl, in
particular thien-2- or 3-yl; pyrrolyl (azolyl), in particular
pyrrol-2- or 3-yl; oxazolyl, in particular oxazol-2,4- or 5-yl;
thiazolyl, in particular thiazol-2,4- or 5-yl; isoxazolyl, in
particular isoxazol-3,4- or 5-yl; isothiazolyl, in particular
isothiazol-3-, 4- or 5-yl; and thiadiazolyl, in particular
1,2,3-thiadiazol-4- or 5-yl, or 1,3,4-thiadiazol-2-yl.
[0134] Most preferred 5 membered heteroaryl groups of the invention
include furanyl, in particular furan-2- or 3-yl; and thienyl, in
particular thien-2- or 3-yl.
[0135] More preferred 6 membered heteroaryl groups of the invention
include pyridyl, in particular pyrid-2-, 3- or 4-yl; and pyrazinyl,
in particular pyrazin-2- or 3-yl.
[0136] In the context of this invention an aromatic bicyclic
heterocyclic group designates a bicyclic heterocyclic group, which
holds one or more heteroatoms in its ring structure. In the context
of this invention the term "bicyclic heterocyclic group" includes
benzo-fused five- and six-membered heterocyclic rings containing
one or more heteroatoms. Preferred heteroatoms include nitrogen
(N), oxygen (O), and sulphur (S).
[0137] Preferred bicyclic heteroaryl groups of the invention
include indolizinyl, in particular indolizin-2-, 5- or 6-yl;
indolyl, in particular indol-2-, 5- or 6-yl; isoindolyl, in
particular isoindol-2-, 5- or 6-yl; benzo[b]furanyl, in particular
benzofuran-2-, 5- or 6-yl; benzo[b]thienyl, in particular
benzothien-2-, 5- or 6-yl; benzoimidazolyl, in particular
benzoimidazol-2-, 5- or 6-yl; benzothiazolyl, in particular
benzothiazol-5- or 6-yl; purinyl, in particular purin-2- or 8-yl;
quinolinyl, in particular quinolin-2-, 3-, 6- or 7-yl;
isoquinolinyl, in particular isoquinolin-3-, 6- or 7-yl;
cinnolinyl, in particular cinnolin-6- or 7-yl; phthalazinyl, in
particular phthalazin-6- or 7-yl; quinazolinyl, in particular
quinazolin-2-, 6- or 7-yl; quinoxalinyl, in particular
quinoxalin-2- or 6-yl; 1,8-naphthyridinyl, in particular
1,8-naphthyridin-2-, 3-, 6- or 7-yl; and pteridinyl, in particular
pteridin-2-, 6- or 7-yl.
[0138] More preferred bicyclic heteroaryl groups of the invention
include indolyl, in particular indol-2-, 5- or 6-yl;
benzo[b]furanyl, in particular benzofuran-2-, 5- or 6-yl;
benzo[b]thienyl, in particular benzothien-2-, 5- or 6-yl;
benzoimidazolyl, in particular benzoimidazol-2-, 5- or 6-yl; and
quinoxalinyl, in particular quinoxalin-2- or 6-yl.
[0139] Most preferred bicyclic heteroaryl groups of the invention
include indolyl, in particular indol-2-, 5- or 6-yl;
benzo[b]furanyl, in particular benzofuran-2-, 5- or 6-yl;
benzo[b]thienyl, in particular benzothien-2-, 5- or 6-yl.
[0140] In the context of this invention a heteroaryloxy group
designates a "heteroaryl-O--" group, wherein heteroaryl is as
defined above.
Pharmaceutically Acceptable Salts
[0141] The diazabicyclic aryl derivative of the invention may be
provided in any form suitable for the intended administration.
Suitable forms include pharmaceutically (i.e. physiologically)
acceptable salts, and pre- or prodrug forms of the chemical
compound of the invention.
[0142] Examples of pharmaceutically acceptable addition salts
include, without limitation, the non-toxic inorganic and organic
acid addition salts such as the hydrochloride derived from
hydrochloric acid, the hydrobromide derived from hydrobromic acid,
the nitrate derived from nitric acid, the perchlorate derived from
perchloric acid, the phosphate derived from phosphoric acid, the
sulphate derived from sulphuric acid, the formate derived from
formic acid, the acetate derived from acetic acid, the aconate
derived from aconitic acid, the ascorbate derived from ascorbic
acid, the benzenesulphonate derived from benzensulphonic acid, the
benzoate derived from benzoic acid, the cinnamate derived from
cinnamic acid, the citrate derived from citric acid, the embonate
derived from embonic acid, the enantate derived from enanthic acid,
the fumarate derived from fumaric acid, the glutamate derived from
glutamic acid, the glycolate derived from glycolic acid, the
lactate derived from lactic acid, the maleate derived from maleic
acid, the malonate derived from malonic acid, the mandelate derived
from mandelic acid, the methanesulphonate derived from methane
sulphonic acid, the naphthalene-2-sulphonate derived from
naphtalene-2-sulphonic acid, the phthalate derived from phthalic
acid, the salicylate derived from salicylic acid, the sorbate
derived from sorbic acid, the stearate derived from stearic acid,
the succinate derived from succinic acid, the tartrate derived from
tartaric acid, the toluene-p-sulphonate derived from p-toluene
sulphonic acid, and the like. Such salts may be formed by
procedures well known and described in the art.
[0143] Other acids such as oxalic acid, which may not be considered
pharmaceutically acceptable, may be useful in the preparation of
salts useful as intermediates in obtaining a chemical compound of
the invention and its pharmaceutically acceptable acid addition
salt.
[0144] Metal salts of a chemical compound of the invention include
alkali metal salts, such as the sodium salt of a chemical compound
of the invention containing a carboxy group.
[0145] Examples of pharmaceutically acceptable cationic salts of a
chemical compound of the invention include, without limitation, the
sodium, the potassium, the calcium, the magnesium, the zinc, the
aluminium, the lithium, the choline, the lysine, and the ammonium
salt, and the like, of a chemical compound of the invention
containing an anionic group. Such cationic salts may be formed by
procedures well known and described in the art.
[0146] In the context of this invention the "onium salts" of
N-containing compounds are also contemplated as pharmaceutically
acceptable salts (aza-onium salts). Preferred aza-onium salts
include the alkyl-onium salts, in particular the methyl- and the
ethyl-onium salts; the cycloalkyl-onium salts, in particular the
cyclopropyl-onium salts; and the cycloalkylalkyl-onium salts, in
particular the cyclopropyl-methyl-onium salts.
[0147] Particularly preferred onium salts of the invention include
those created at the N' position according to the following Formula
I'
##STR00007##
Steric Isomers
[0148] The chemical compounds of the present invention may exist in
(+) and (-) forms as well as in racemic forms. The racemates of
these isomers and the individual isomers themselves are within the
scope of the present invention.
[0149] Racemic forms can be resolved into the optical antipodes by
known methods and techniques. One way of separating the
diastereomeric salts is by use of an optically active acid, and
liberating the optically active amine compound by treatment with a
base. Another method for resolving racemates into the optical
antipodes is based upon chromatography on an optical active matrix.
Racemic compounds of the present invention can thus be resolved
into their optical antipodes, e.g., by fractional crystallisation
of d- or l- (tartrates, mandelates, or camphorsulphonate) salts for
example.
[0150] The chemical compounds of the present invention may also be
resolved by the formation of diastereomeric amides by reaction of
the chemical compounds of the present invention with an optically
active activated carboxylic acid such as that derived from (+) or
(-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic
acid or by the formation of diastereomeric carbamates by reaction
of the chemical compound of the present invention with an optically
active chloroformate or the like.
[0151] Additional methods for the resolving the optical isomers are
known in the art. Such methods include those described by Jaques J,
Collet A, & Wilen S in "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, New York (1981).
[0152] Optical active compounds can also be prepared from optical
active starting materials.
Methods of Producing Diazabicyclic Aryl Derivatives
[0153] The diazabicyclic aryl derivative of the invention may be
prepared by conventional methods for chemical synthesis, e.g. those
described in the working examples. The starting materials for the
processes described in the present application are known or may
readily be prepared by conventional methods from commercially
available chemicals.
[0154] Also one compound of the invention can be converted to
another compound of the invention using conventional methods.
[0155] The end products of the reactions described herein may be
isolated by conventional techniques, e.g. by extraction,
crystallisation, distillation, chromatography, etc.
Biological Activity
[0156] The present invention is devoted to the provision novel
ligands and modulators of the nicotinic receptors, which ligands
and modulators are useful for the treatment of diseases or
disorders related to the cholinergic receptors, and in particular
the nicotinic acetylcholine receptor (nAChR). Preferred compounds
of the invention show a pronounced nicotinic acetylcholine .alpha.7
receptor subtype selectivity.
[0157] The compounds of the present invention may in particular be
agonists, partial agonists, antagonists and/or allosteric
modulators of the nicotinic acetylcholine receptor.
[0158] Due to their pharmacological profile the compounds of the
invention may be useful for the treatment of diseases or disorders
as diverse as those related to the cholinergic system of the
central nervous system (CNS), the peripheral nervous system (PNS),
diseases or disorders related to smooth muscle contraction,
endocrine diseases or disorders, diseases or disorders related to
neuro-degeneration, diseases or disorders related to inflammation,
pain, and withdrawal symptoms caused by the termination of abuse of
chemical substances.
[0159] The compounds of the invention may also be useful as
diagnostic tools or monitoring agents in various diagnostic
methods, and in particular for in vivo receptor imaging
(neuroimaging), and they may be used in labelled or unlabelled
form.
[0160] In a preferred embodiment the compounds of the invention are
used for the treatment of diseases, disorders, or conditions
relating to the central nervous system. Such diseases or disorders
includes anxiety, cognitive disorders, learning deficit, memory
deficits and dysfunction, Alzheimer's disease, attention deficit,
attention deficit hyperactivity disorder (ADHD), Parkinson's
disease, Huntington's disease, Amyotrophic Lateral Sclerosis,
Gilles de la Tourette's syndrome, psychosis, depression, mania,
manic depression, schizophrenia, obsessive compulsive disorders
(OCD), panic disorders, eating disorders such as anorexia nervosa,
bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile
dementia, periferic neuropathy, autism, dyslexia, tardive
dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic
syndrome, social phobia, sleeping disorders, pseudodementia,
Ganser's syndrome, pre-menstrual syndrome, late luteal phase
syndrome, chronic fatigue syndrome, mutism, trichotillomania, and
jet-lag.
[0161] In a preferred embodiment diseases, disorders, or conditions
relating to the central nervous system for which the compounds of
the invention are used are cognitive disorders, psychosis,
schizophrenia and/or depression.
[0162] In another preferred embodiment the compounds of the
invention may be useful for the treatment of diseases, disorders,
or conditions associated with smooth muscle contractions, including
convulsive disorders, angina pectoris, premature labour,
convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia,
hyperkinesia, premature ejaculation, and erectile difficulty.
[0163] In yet another preferred embodiment the compounds of the
invention may be useful for the treatment of endocrine disorders,
such as thyrotoxicosis, pheochromocytoma, hypertension and
arrhythmias.
[0164] In still another preferred embodiment the compounds of the
invention may be useful for the treatment of neurodegenerative
disorders, including transient anoxia and induced
neuro-degeneration.
[0165] In even another preferred embodiment the compounds of the
invention may be useful for the treatment of inflammatory diseases,
disorders, or conditions, including inflammatory skin disorders
such as acne and rosacea, Chron's disease, inflammatory bowel
disease, ulcerative colitis, and diarrhea.
[0166] In still another preferred embodiment the compounds of the
invention may be useful for the treatment of mild, moderate or even
severe pain of acute, chronic or recurrent character, as well as
pain caused by migraine, postoperative pain, and phantom limb pain.
The pain may in particular be neuropathic pain, chronic headache,
central pain, pain related to diabetic neuropathy, to post
therapeutic neuralgia, or to peripheral nerve injury.
[0167] Finally the compounds of the invention may be useful for the
treatment of withdrawal symptoms caused by termination of use of
addictive substances. Such addictive substances include nicotine
containing products such as tobacco, opioids such as heroin,
cocaine and morphine, benzodiazepines and benzodiazepine-like
drugs, and alcohol. Withdrawal from addictive substances is in
general a traumatic experience characterised by anxiety and
frustration, anger, anxiety, difficulties in concentrating,
restlessness, decreased heart rate and increased appetite and
weight gain.
[0168] In this context "treatment" covers treatment, prevention,
prophylactics and alleviation of withdrawal symptoms and abstinence
as well as treatment resulting in a voluntary diminished intake of
the addictive substance.
[0169] In another aspect, the compounds of the invention are used
as diagnostic agents, e.g. for the identification and localisation
of nicotinic receptors in various tissues.
Pharmaceutical Compositions
[0170] In another aspect the invention provides novel
pharmaceutical compositions comprising a therapeutically effective
amount of the diazabicyclic aryl derivative of the invention.
[0171] While a chemical compound of the invention for use in
therapy may be administered in the form of the raw chemical
compound, it is preferred to introduce the active ingredient,
optionally in the form of a physiologically acceptable salt, in a
pharmaceutical composition together with one or more adjuvants,
excipients, carriers, buffers, diluents, and/or other customary
pharmaceutical auxiliaries.
[0172] In a preferred embodiment, the invention provides
pharmaceutical compositions comprising the diazabicyclic aryl
derivative of the invention, or a pharmaceutically acceptable salt
or derivative thereof, together with one or more pharmaceutically
acceptable carriers therefore, and, optionally, other therapeutic
and/or prophylactic ingredients, know and used in the art. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not harmful to
the recipient thereof.
[0173] The pharmaceutical composition of the invention may be
administered by any convenient route, which suits the desired
therapy. Preferred routes of administration include oral
administration, in particular in tablet, in capsule, in drage in
powder, or in liquid form, and parenteral administration, in
particular cutaneous, subcutaneous, intramuscular, or intravenous
injection. The pharmaceutical composition of the invention can be
manufactured by the skilled person by use of standard methods and
conventional techniques appropriate to the desired formulation.
When desired, compositions adapted to give sustained release of the
active ingredient may be employed.
[0174] The diazabicyclic aryl derivative of the invention can be
administered in a wide variety of oral and parenteral dosage forms.
It will be obvious to those skilled in the art that the following
dosage forms may comprise, as the active component, either a
chemical compound of the invention or a pharmaceutically acceptable
salt of a chemical compound of the invention.
[0175] When desired, compositions adapted to give sustained release
of the active ingredient may be employed.
[0176] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packaged
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0177] Tablets or capsules for oral administration and liquids for
intravenous administration and continuous infusion are preferred
compositions.
[0178] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0179] A therapeutically effective dose refers to that amount of
active ingredient, which ameliorates the symptoms or condition.
Therapeutic efficacy and toxicity, e.g. ED.sub.50 and LD.sub.50,
may be determined by standard pharmacological procedures in cell
cultures or experimental animals. The dose ratio between
therapeutic and toxic effects is the therapeutic index and may be
expressed by the ratio LD.sub.50/ED.sub.50. Pharmaceutical
compositions exhibiting large therapeutic indexes are
preferred.
[0180] The dose administered must of course be carefully adjusted
to the age, weight and condition of the individual being treated,
as well as the route of administration, dosage form and regimen,
and the result desired, and the exact dosage should of course be
determined by the practitioner.
[0181] The actual dosage depend on the nature and severity of the
disease being treated, and is within the discretion of the
physician, and may be varied by titration of the dosage to the
particular circumstances of this invention to produce the desired
therapeutic effect. However, it is presently contemplated that
pharmaceutical compositions containing of from about 0.1 to about
500 mg of active ingredient per individual dose, preferably of from
about 1 to about 100 mg, most preferred of from about 1 to about 10
mg, are suitable for therapeutic treatments.
[0182] The active ingredient may be administered in one or several
doses per day. A satisfactory result can, in certain instances, be
obtained at a dosage as low as 0.1 .mu.g/kg i.v. and 1 .mu.g/kg
p.o. The upper limit of the dosage range is presently considered to
be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from
about 0.1 .mu.g/kg to about 10 mg/kg/day i.v., and from about 1
.mu.g/kg to about 100 mg/kg/day p.o.
Methods of Therapy
[0183] The diazabicyclic aryl derivatives of the present invention
are valuable nicotinic receptor modulators, and therefore useful
for the treatment of a range of ailments involving cholinergic
dysfunction as well as a range of disorders responsive to the
action of nAChR modulators.
[0184] In another aspect the invention provides a method for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disease, disorder or condition is responsive to modulation of
cholinergic receptors, and which method comprises administering to
such a living animal body, including a human, in need thereof an
effective amount of a diazabicyclic aryl derivative of the
invention.
[0185] In the context of this invention the term "treatment" covers
treatment, prevention, prophylaxis or alleviation, and the term
"disease" covers illnesses, diseases, disorders and conditions
related to the disease in question.
[0186] The preferred indications contemplated according to the
invention are those stated above.
[0187] It is at present contemplated that suitable dosage ranges
are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and
especially 30-100 milligrams daily, dependent as usual upon the
exact mode of administration, form in which administered, the
indication toward which the administration is directed, the subject
involved and the body weight of the subject involved, and further
the preference and experience of the physician or veterinarian in
charge.
[0188] A satisfactory result can, in certain instances, be obtained
at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The
upper limit of the dosage range is about 10 mg/kg i.v. and 100
mg/kg p.o. Preferred ranges are from about 0.001 to about 1 mg/kg
i.v. and from about 0.1 to about 10 mg/kg p.o.
EXAMPLES
[0189] The invention is further illustrated with reference to the
following examples, which are not intended to be in any way
limiting to the scope of the invention as claimed.
Example 1
Preparatory Example
[0190] All reactions involving air sensitive reagents or
intermediates were performed under nitrogen and in anhydrous
solvents.
1,4-Diazabicyclo[3.2.2]nonan-3-one (Intermediate Compound)
[0191] 32.33 g (200 mmol) of 3-Quinuclidinone hydrochloride was
dissolved in 75 ml of water, and to the solution of hydroxylamine
hydrochloride (16.4 g; 236 mmol) and CH.sub.3CO.sub.2Na.3H.sub.2O
(80 g; 588 mmol) was added. The mixture was stirred at 70.degree.
C. for 1 hour. Then NaCl (10 g) was dissolved in the mixture and
was cooled to 0.degree. C. Separated crystals were filtered and
carefully dried. The obtained crude 3-quinuclidone oxime (approx.
30 g) was used in the next step of the synthesis without further
purification.
[0192] Polyphosphoric acid (180 g) of was heated to 100.degree. C.
and crude 3-quinuclidone oxime (30 g) was added portionwise. The
reaction mixture was heated at 130.degree. C. for 20 minutes. The
mixture was cooled to room temperature, and 50 ml of water was
added. The mass was carefully homogenised, the mixture was poured
into of ice (100 g). The mixture was made alkaline (pH 12) by
adding sodium hydroxide. The mixture was extracted with chloroform
(2.times.400 ml). The extract was dried over sodium sulphate and
the solvent was removed under reduced pressure.
[0193] Yield of the mixture of the products
1,4-diazabicyclo[3.2.2]nonan-3-one and
1,3-diazabicyclo[3.2.2]nonan-4-one was 19.02 g (68%). The mixture
of isomers was crystallized from 80 ml of dioxane to yield
1,4-diazabicyclo[3.2.2]nonan-3-one (5.12 g; 18%). The solvent from
filtrate was distilled off, flash chromatography (with acetone) of
the residue gave of 1,3-diazabicyclo[3.2.2]nonan-4-one (8.91 g
32%).
1,4-Diazabicyclo[3.2.2]nonane [J. Med. Chem. 1993 36 2311-2320]
(Intermediate Compound)
[0194] 1,4-Diazabicyclo[3.2.2]nonan-3-one (5.12 g; 36 mmol) was
dissolved in tetrahydrofuran (50 ml), lithium aluminium hydride
2.28 g (60 mmol) was added to the solution and the reaction mixture
was refluxed for 36 hours. After cooling the reaction mixture to
room temperature, water (2.3 ml) was added dropwise and the mixture
was filtered. The solvent was removed from the filtrate by
rotavapor at reduced pressure. The formed substance was distilled
with Kugelrohr (0.5 mBar, 70.degree. C.). Yield of the title
compound 3.11 g (68%).
3-Bromo-2-furoic acid (Intermediate Compound)
[0195] To a mixture of 3-bromo furan (51.0 g; 0.347 mol) and THF
(250 ml) was added lithiumdiisopropylamide (191 ml; 0.382 mol; 2M
solution in heptane/THF/ethylbenzene) at -70.degree. C. The mixture
was stirred for 1 hour at -70.degree. C. Solid carbondioxide (100.3
g; 2.28 mol) was added and the mixture was stirred until the
carbondioxide was gone. Water (50 ml) was added followed by aqueous
hydrochloric acid (380 ml; 2M). The tetrahydrofuran was evaporated.
The mixture was extracted with diethylether (3.times.100 ml). The
combined ether phase was extracted with aqueous sodium hydroxide
(3.times.100 ml; 2M). The aqueous phase was cooled on ice and
acidified with aqueous hydrochloric acid (100 ml; 10M). The mixture
was extracted with ether (3.times.100 ml). The combined ether phase
was evaporated. Yield 36 g (54%). Mp. 118.5.degree. C.
Method A
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-furan-2-yl-methanone
hydrochloric acid salt (Compound A1)
[0196] A mixture of 1,4-Diaza-bicyclo[3.2.2]nonane (0.50 g; 4.0
mmol), 2-furoyl chloride (0.52 mg; 4.0 mmol), diisopropylethylamine
(1.02 g; 7.9 mmol) and 1,2-dimethoxyethane (25 ml) was stirred at
room-temperature over night. The product precipitated as
hydrochloric acid salt and was filtered and washed with
1,2-dimethoxyethane (5 ml). Yield 0.84 g (82%). Mp. 279-283.degree.
C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-bromo-furan-2-yl-methanone
fumaric acid salt (Compound A2)
[0197] The title compound was prepared according to Method A, from
5-bromo-2-furoyl chloride (Method B) using no
diisopropylethylamine. Aqueous sodium hydroxide (10 ml; 1M) was
added. The mixture was extracted with dichloromethane (3.times.10
ml). Chromatography on silica gel with dichloromethane, methanol
and conc. ammonia (89:10:1) gave the title compound. The
corresponding salt was obtained by addition of a diethyl ether and
methanol mixture (9:1) saturated with fumaric acid. Mp.
192.7-196.4.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-nitro-furan-2-yl-methanone
hydrochloric acid salt (Compound A3)
[0198] The title compound was prepared according to Method A, from
5-nitro-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 242.6-251.0.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone
hydrochloric acid salt (Compound A4)
[0199] The title compound was prepared according to Method A from
5-(4-nitrophenyl)-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 298.2.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-O-trifluoromethylphenyl)-furan-2-yl-m-
ethanone hydrochloric acid salt (Compound A5)
[0200] The title compound was prepared according to Method A from
5-(3-trifluoromethylphenyl)-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 236.9.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-chlorophenyl)-furan-2-yl-methanone
hydrochloric acid salt (Compound A6)
[0201] The title compound was prepared according to Method A from
5-(4-chlorophenyl)-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 272.5-274.7.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanone
hydrochloric acid salt (Compound A7)
[0202] The title compound was prepared according to Method A from
5-(2-nitrophenyl)-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 216.3-219.9.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-methanone
hydrochloric acid salt (Compound A8)
[0203] The title compound was prepared according to Method A from
5-(3-nitrophenyl)-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 224-230.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-8-methoxy-benzofuran-2-yl-methanone
hydrochloric acid salt (Compound A9)
[0204] The title compound was prepared according to Method A from
8-methoxy-2-benzofuroyl chloride (Method B), using no
diisopropylethylamine. Mp. 241-246.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-oxazolyl-5-yl-methanone
hydrochloric acid salt (Compound A10)
[0205] The title compound was prepared according to Method A from
5-oxazoloyl chloride (Method B), using no diisopropylethylamine.
Mp.>160.degree. C. (decomp.).
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzofuran-2-yl-methanone
hydrochloric acid salt (Compound A11)
[0206] The title compound was prepared according to Method A from
2-benzofuroyl chloride (Method B), using no diisopropylethylamine.
Mp. 264.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-furan-2-yl-methanone
hydrochloric acid salt (Compound A12)
[0207] The title compound was prepared according to Method A from
3-methyl-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 225.8-227.2.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-4,5-dibromo-furan-2-yl-methanone
fumaric acid salt (Compound A13)
[0208] The title compound was prepared according to Method A from
4,5-dibromo-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 250.9-254.3.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-chloro-5-trifluoromethylphenyl)-fu-
ran-2-yl-methanone hydrochloric acid salt (Compound A14)
[0209] The title compound was prepared according to Method A from
5-(2-chloro-5-trifluoromethylphenyl)-2-furoyl chloride (Method B),
using no diisopropylethylamine. Mp. 201.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-methylphenyl)-furan-2-yl-m-
ethanone hydrochloric acid salt (Compound A15)
[0210] The title compound was prepared according to Method A from
5-(2-nitro-4-methylphenyl)-2-furoyl chloride (Method B), using no
diisopropylethylamine. Mp. 199.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-benzofuran-2-yl-methanone
hydrochloric acid salt (Compound A16)
[0211] The title compound was prepared according to Method A from
3-methyl-2-benzofuroyl chloride (Method B), using no
diisopropylethylamine. Mp. 260-276.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenyl-1,3,4-oxadiazol-2-yl-methanone
hydrochloric acid salt (Compound A17)
[0212] The title compound was prepared according to Method A from
5-methyl-1,3,4-oxadiazol-2-carbonyl-chloride chloride, using no
diisopropylethylamine. Mp. 280-290.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-meth-
anone hydrochloric acid salt (Compound A18)
[0213] The title compound was prepared according to Method A from
5-(3,5-dichlorophenoxy)-furan-2-carbonyl chloride, using no
diisopropylethylamine. Mp. 124.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiome-
thyl]-furan-2-yl-methanone hydrochloric acid salt (Compound
A19)
[0214] The title compound was prepared according to Method A from
5-[5-(trifluoromethyl-2-pyridyl)-thiomethyl]-furan-2-carbonyl
chloride, using no diisopropylethylamine. Mp. 176.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-bromo-furan-2-yl-methanone
fumaric acid salt (Compound A20)
[0215] The title compound was prepared according to Method A, from
3-bromo-2-furoyl chloride (Method B from 3-bromo-2-furoic acid)
using no diisopropylethylamine. Mp. 157.4-159.9.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanone
fumaric acid salt (Compound A21)
[0216] The title compound was prepared according to Method A, from
5-(2-phenylethynyl)-2-furanoic acid chloride. Mp.
166.3-168.3.degree. C.
Method B
3-Bromo-2-furoic acid (Intermediate Compound)
[0217] To a mixture of 3-bromo furan (51.0 g; 0.347 mol) and THF
(250 ml) was added lithiumdiisopropylamide (191 ml; 0.382 mol; 2 M
solution in heptane/THF/ethylbenzene) at -70.degree. C. The mixture
was stirred for 1 hour at -70.degree. C. Solid carbondioxide (100.3
g; 2.28 mol) was added and the mixture was stirred until the
carbondioxide was gone. Water (50 ml) was added followed by aqueous
hydrochloric acid (380 ml; 2M). The tetrahydrofuran was evaporated.
The mixture was extracted with diethylether (3.times.100 ml). The
combined ether phase was extracted with aqueous sodium hydroxide
(3.times.100 ml; 2M). The aqueous phase was cooled on ice and
acidified with aqueous hydrochloric acid (100 ml; 10M). The mixture
was extracted with ether (3.times.100 ml). The combined ether phase
was evaporated. Yield 36 g (54%). Mp. 118.5.degree. C.
5-(4-nitrophenyl)-2-furoyl chloride (Intermediate Compound)
[0218] The title compound was prepared by stirring a mixture of
5-(4-nitrophenyl)-2-furoic acid (1.0 g; 4.3 mmol) and thionyl
chloride (10 ml) at reflux for 2 hours. The mixture was evaporated
and co-evaporated with anhydrous toluene. The acid chloride was
used without further purification.
Method C
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
fumaric acid salt (Compound C1)
[0219] A mixture of
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone
(0.70 g; 1.9 mmol), palladium on carbon (400 mg; 5%) and ethanol
(30 ml) was stirred under hydrogen for 24 hours. The mixture was
filtered through celite and evaporated. Yield 0.44 g (74%). The
corresponding salt was obtained by addition of a diethyl ether and
methanol mixture (9:1) saturated with fumaric acid. Mp.
227.8.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-aminophenyl)-furan-2-yl-methanone
fumaric acid salt (Compound C2)
[0220] The title compound was prepared according to Method C from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanone-
. Mp. 201.1-207.3.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-aminophenyl)-furan-2-yl-methanone
fumaric acid salt (Compound C3)
[0221] The title compound was prepared according to Method C from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-methanone-
. Mp. 184.9-188.2.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-amino-4-methylphenyl)-furan-2-yl-m-
ethanone fumaric acid salt (Compound C4)
[0222] The title compound was prepared according to Method C from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-methylphenyl)-furan-2-yl--
methanone. Mp. 179.degree. C.
Method D
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-acetylaminophenyl)-furan-2-yl-meth-
anone (Compound D1)
[0223] Acetic acid anhydride (133 mg; 1.3 mmol) solved in
dichloromethane (2 ml) was added dropwise to a mixture of
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
and dichloromethane (10 ml) at room temperature. The mixture was
allowed to stir for 4 hours. Aqueous sodium hydroxide (20 ml; 1M)
was added followed by extraction with dichloromethane (3.times.20
ml). The crude mixture was purified by silica gel chromatography,
using a mixture of dichloromethane:methanol (4:1) and 2% methanol
as eluent. The product was isolated as the free base. Mp.
113.degree. C. (decomp.).
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(2-acetylaminophenyl)-furan-2-yl-meth-
anone fumaric acid salt (Compound D2)
[0224] The title compound was prepared according to Method D from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-aminophenyl)-furan-2-yl-methanone-
. The corresponding salt was obtained by addition of a diethyl
ether and methanol mixture (9:1) saturated with fumaric acid. Mp.
178.9-185.0.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(3-acetylaminophenyl)-furan-2-yl-meth-
anone fumaric acid salt (Compound D3)
[0225] The title compound was prepared according to Method D from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-aminophenyl)-furan-2-yl-methanone-
. The corresponding salt was obtained by addition of a diethyl
ether and methanol mixture (9:1) saturated with fumaric acid. Mp.
216.degree. C.
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-pr-
opionamide free base (Compound D4)
[0226] The title compound was prepared according to Method D from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone-
. Mp. 264.degree. C.
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-2,-
2,2-trifluoro-acetamide trifluoro acetic acid salt (Compound
D5)
[0227] The title compound was prepared according to Method D from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
and trifluoroacetic anhydride. Mp. 219.degree. C.
[0228]
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phe-
nyl}-isobutyramide fumaric acid salt (Compound D6)
[0229] The title compound was prepared according to Method D from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
and isobutyric anhydride. Mp. 223.degree. C.
Method E
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-dimethylsulfonyl)aminophenyl]-
-furan-2-yl-methanone free base (Compound E1)
[0230] A mixture of
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
(0.5 g; 1.6 mmol) and dichloromethane (5 ml), methanesulfonyl
chloride (2.12 g; 18.4 mmol) and dichloromethane (5 ml) was stirred
at room temperature for 15 hours. Aqueous sodium hydroxide (5 ml;
1M) was added followed by extraction with dichloromethane
(3.times.5 ml). The crude mixture was purified by silica gel
chromatography, using a mixture of dichloromethane:methanol (9:1)
and 1% methanol as eluent. The product was isolated as the free
base. Yield 20 mg (3%). Mp. 189.degree. C.
N-{4-[(5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-a-
crylamide fumaric acid salt (Compound E2)
[0231] The title compound was prepared according to Method E from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
and acryloyl chloride (1.6 eq.). Mp. 220.degree. C.
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-be-
nzamide fumaric acid salt (Compound E3)
[0232] The title compound was prepared according to Method E from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone-
, diisopropylethylamine (2 eq.) and benzoyl chloride (1.5 eq.). Mp.
254.degree. C.
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-diphenylsulfonylamino)phenyl]-
-furan-2-yl-methanone fumaric acid salt (Compound E4)
[0233] The title compound was prepared according to Method E from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone-
, diisopropylethylamine (2 eq.) and benzenesulfonyl chloride (1.5
eq.). Mp. 201-203.degree. C.
[0234] Cyclopropanecarboxylic acid
{4-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-ami-
de fumaric acid salt (Compound E5)
[0235] The title compound was prepared according to Method E from
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone-
, cyclopropanecarbonyl chloride. Mp. 254.degree. C.
Method F
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-formylaminophenyl)-furan-2-yl-meth-
anone (Compound F1)
[0236] A mixture of
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
(0.50 g; 1.6 mmol) and ethylformate (30 ml) was stirred at reflux
for 9 days. The mixture was evaporated. Aqueous sodium hydroxide
(20 ml; 1 M) was added followed by extraction with dichloromethane
(3.times.20 ml). The crude mixture was purified by silica gel
chromatography, using a mixture of dichloromethane:methanol (9:1)
and 1% methanol as eluent. The product was isolated as the free
base. Yield 0.29 g (53%). Mp. 236.degree. C.
Method G
(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
chloromethylium chloride salt (Compound G1)
[0237] Ethylisothiocyanate (182 mg; 2.09 mmol) solved in
dichloromethane (20 ml) was added dropwise to a mixture of
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone
and dichloromethane (10 ml) at 5.degree. C. The mixture was allowed
to stir for 4 hours at 5.degree. C. and 11 hours at room
temperature. The solvent volume was reduced to a third and the
solid product was isolated by filtration. Mp.>300.degree. C.
Method H
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-ac-
rylamide methylium iodide (Compound H1)
[0238] A mixture of
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-a-
crylamide (175 mg; 0.479 mmol) and dichloromethane (10 ml) was
stirred at -70.degree. C. Iodomethane (68 mg (0.479 mmol) solved in
dichloromethane (5 ml) was added. The mixture was allowed to stir
at -70.degree. C. for 1 hour. The mixture was allowed to reach room
temperature and was evaporated and triturated with diethylether.
Yield 0.15 g (62%). Mp. 230-246.degree. C.
Method I
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-ac-
rylamide N-oxide (Compound I1)
[0239] A mixture of
N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-a-
crylamide (175 mg; 0.479 mmol), m-chloroperoxybenzoic acid (165 mg;
0.958 mmol) and dichloromethane (5 ml) was stirred at
room-temperature for 15 hours. The crude mixture was evaporated.
Chromatography on silica gel with dichloromethane, methanol and
conc. ammonia (89:10:1) gave the title compound. Yield 180 mg
(99%). Mp. 162.degree. C.
Example 2
In Vitro Inhibition of .sup.3H-.alpha.-Bungarotoxine Binding in Rat
Brain
[0240] In this example the affinity of the compounds of the
invention for binding to .alpha..sub.7-subtype of nicotinic
receptors is determined.
[0241] .alpha.-Bungarotoxine is a peptide isolated from the venom
of the Elapidae snake Bungarus multicinctus. It has high affinity
for neuronal and neuromuscular nicotinic receptors, where it acts
as a potent antagonist. .sup.3H-.alpha.-Bungarotoxine labels
nicotinic acetylcholine receptors formed by the .alpha..sub.7
subunit isoform found in brain and the .alpha..sub.1 isoform in the
neuromuscular junction.
Tissue Preparation
[0242] Preparations are performed at 0-4.degree. C. Cerebral
cortices from male Wistar rats (150-250 g) are homogenised for 10
seconds in 15 ml of 20 mM Hepes buffer containing 118 mM NaCl, 4.8
mM KCl, 1.2 mM MgSO.sub.4 and 2.5 mM CaCl.sub.2 (pH 7.5) using an
Ultra-Turrax homogeniser. The tissue suspension is subjected to
centrifugation at 27,000.times.g for 10 minutes. The supernatant is
discarded and the pellet is washed twice by centrifugation at
27,000.times.g for 10 minutes in 20 ml of fresh buffer, and the
final pellet is then re-suspended in fresh buffer containing 0.01%
BSA (35 ml per g of original tissue) and used for binding
assays.
Assay
[0243] Aliquots of 500 .mu.l of homogenate are added to 25 .mu.l of
test solution and 25 .mu.l of .sup.3H-.alpha.-bungarotoxine (2 nM,
final concentration) and mixed and incubated for 2 hours at
37.degree. C. Non-specific binding is determined using (-)-nicotine
(1 mM, final concentration). After incubation, the samples are
added 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poured
directly onto Whatman GF/C glass fibre filters (pre-soaked in 0.1%
PEI for at least 6 hours) under suction, and immediately washed
with 2.times.5 ml ice-cold buffer.
[0244] The amount of radioactivity on the filters is determined by
conventional liquid scintillation counting. Specific binding is
total binding minus non-specific binding.
[0245] The test value is given as an IC.sub.50 (the concentration
of the test substance which inhibits the specific binding of
.sup.3H-.alpha.-bungarotoxin by 50%).
[0246] The results of these experiments are presented in Table 1
below.
TABLE-US-00001 TABLE 1 Inhibition of .sup.3H-.alpha.-Bungarotoxine
Binding Compound IC.sub.50 No. (.mu.M) A1 0.54 A5 0.051 C3 0.080 F1
0.017
* * * * *