U.S. patent application number 11/890230 was filed with the patent office on 2008-02-07 for pyrazolopyrimidines, a process for their preparation and their use as medicine.
This patent application is currently assigned to MERZ PHARMA GMBH & CO. KGAA. Invention is credited to Wojciech Danysz, Andrzej Dekundy, Juris Fotins, Aleksandrs Gutcaits, Mirko Hechenberger, Markus Henrich, Claudia Jatzke, Ivars Kalvinsh, Valerjans Kauss, Jens Nagel, Christopher Graham Raphael Parsons, Tanja Weil, Ronalds Zemribo.
Application Number | 20080032998 11/890230 |
Document ID | / |
Family ID | 38710494 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080032998 |
Kind Code |
A1 |
Danysz; Wojciech ; et
al. |
February 7, 2008 |
Pyrazolopyrimidines, a process for their preparation and their use
as medicine
Abstract
Substituted pyrazolopyrimidine derivatives of formula (I)
##STR1## wherein R.sup.1 represents chloro or bromo; R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently
represent e.g. hydrogen or C.sub.1-6-alkyl; R.sup.8 represents a
radical R.sup.9 or a radical R.sup.10, whereby one of the two
radicals R.sup.8 represents R.sup.9 and the other radical R.sup.8
represents Ret; R.sup.9 represents e.g. a phenyl or thiophene
group, and R.sup.10 represents e.g. hydrogen or methyl; are potent
mGluR5 modulators and are useful for the prevention of acute and
chronic neurological disorders.
Inventors: |
Danysz; Wojciech; (Nidderau,
DE) ; Dekundy; Andrzej; (Schoneck, DE) ;
Hechenberger; Mirko; (Frankfurt, DE) ; Henrich;
Markus; (Munzenberg, DE) ; Jatzke; Claudia;
(Frankfurt/Main, DE) ; Nagel; Jens; (Daxweiler,
DE) ; Parsons; Christopher Graham Raphael; (Nidderau,
DE) ; Weil; Tanja; (Frankfurt/Main, DE) ;
Fotins; Juris; (Riga, LV) ; Gutcaits; Aleksandrs;
(Riga, LV) ; Kalvinsh; Ivars; (Salaspils, LV)
; Zemribo; Ronalds; (Jurmala, LV) ; Kauss;
Valerjans; (Riga, LV) |
Correspondence
Address: |
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING
107 WEST MICHIGAN AVENUE
KALAMAZOO
MI
49007
US
|
Assignee: |
MERZ PHARMA GMBH & CO.
KGAA
FRANKFURT AM MAIN
DE
|
Family ID: |
38710494 |
Appl. No.: |
11/890230 |
Filed: |
August 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60835820 |
Aug 4, 2006 |
|
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|
60877544 |
Dec 28, 2006 |
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Current U.S.
Class: |
514/259.3 ;
544/281 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
25/22 20180101; A61P 37/02 20180101; A61P 1/08 20180101; A61P 25/36
20180101; A61P 43/00 20180101; A61P 25/32 20180101; A61P 25/16
20180101; C07D 487/04 20130101; A61P 35/02 20180101; A61P 25/30
20180101; A61P 29/00 20180101; A61P 27/06 20180101; A61P 9/10
20180101; A61P 1/14 20180101; A61P 19/02 20180101; A61P 25/18
20180101; A61P 31/00 20180101; A61P 3/00 20180101; A61P 25/02
20180101; C07D 519/00 20130101; A61P 9/00 20180101; A61P 17/04
20180101; A61P 25/06 20180101; A61P 27/02 20180101; A61P 37/00
20180101; A61P 25/24 20180101; A61P 25/34 20180101; A61P 1/04
20180101; A61P 21/00 20180101; A61P 11/04 20180101; A61P 35/00
20180101; A61P 3/08 20180101; A61P 25/00 20180101; A61P 25/14
20180101; A61P 25/08 20180101; A61P 27/16 20180101; A61P 11/06
20180101; A61P 21/02 20180101; A61P 1/00 20180101; A61P 13/02
20180101; A61P 25/28 20180101; A61P 11/00 20180101; A61P 25/04
20180101; A61P 25/20 20180101 |
Class at
Publication: |
514/259.3 ;
544/281 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61P 1/00 20060101 A61P001/00; A61P 25/00 20060101
A61P025/00; A61P 3/00 20060101 A61P003/00; A61P 35/00 20060101
A61P035/00; A61P 9/00 20060101 A61P009/00; C07D 239/70 20060101
C07D239/70 |
Claims
1. A compound selected from those of formula (I) ##STR161## wherein
R.sup.1 represents chloro or bromo; R.sup.2 and R.sup.3 each
independently represent hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.2 and R.sup.3 both
together with the carbon atom of the ring represent a carbonyl
group; R.sup.4 and R.sup.5 each independently represent hydrogen,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.4
and R.sup.5 both together with the carbon atom of the ring
represent a carbonyl group; R.sup.6 and R.sup.7 independently
represent hydrogen, C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or R.sup.6 and R.sup.7 both together with the
carbon atom of the ring represent a carbonyl group; R.sup.2 or
R.sup.3 together with R.sup.6 and R.sup.7 may also form a bivalent
radical selected from the group CH.sub.2--CH.sub.2 and CH.sub.2--O;
R.sup.8 represents a radical R.sup.9 or a radical R.sup.10, whereby
one of the two radicals R.sup.8 represents R.sup.9 and the other
radical R.sup.8 represents R.sup.10; R.sup.9 represents a cyclic
group selected from aryl, heteroaryl or heterocyclyl, wherein the
ring system may be optionally substituted by one or two
substituents, which may be the same or different and selected
independently from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; R.sup.10 represents
hydrogen or C.sub.1-6alkyl; and optical isomers, pharmaceutically
acceptable salts, hydrates, solvates, and polymorphs thereof.
2. The compound of claim 1, wherein R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 independently represent hydrogen,
C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; and one of
the radicals R.sup.8 represents hydrogen or methyl and the other
radical R.sup.8 represents a phenyl, thiophene, pyrrole, tetrazole,
furane, pyridine or pyrimidine ring, wherein the ring system may be
substituted by one substituent selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl and
C.sub.1-6alkoxy.
3. The compound of claim 1, wherein one of the radicals R.sup.8
represents hydrogen and the other radical R.sup.8 represents a
phenyl, thiophene, pyrrole, tetrazole, furan, pyridine or
pyrimidine ring which may be optionally substituted by one
substituent selected from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy.
4. The compound of claim 1, wherein R.sup.6 and R.sup.7 represent
hydrogen.
5. The compound of claim 1, wherein R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 independently represent hydrogen, methyl, ethyl or
trifluoromethyl; and R.sup.6 and R.sup.7 independently represent
hydrogen or methyl.
6. The compound of claim 1, wherein R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 independently represent hydrogen,
methyl or ethyl.
7. The compound of claim 1, wherein R.sup.2 and R.sup.3
independently represent hydrogen, methyl or ethyl.
8. The compound of claim 1, wherein R.sup.2 represents methyl or
ethyl and R.sup.3 represents hydrogen and which has at least one
chiral carbon atom.
9. The compound of claim 1, wherein R.sup.2 represents hydrogen or
methyl and R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 represent
hydrogen.
10. The compound of claim 1, wherein R.sup.1 represents chloro.
11. The compound of claim 1, wherein R.sup.1 represents bromo.
12. The compound of claim 1, wherein R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 represent hydrogen.
13. The compound of claim 1, wherein R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 represent hydrogen, and the radical
R.sup.8 which is in 3-position of the dihydro-pyridin-ring system
represents hydrogen.
14. The compound of claim 1, wherein the radical R.sup.8 which is
in 4-position of the dihydro-pyridin-ring represents a phenyl,
thiophene, pyrrole, tetrazole, furan, pyridine or pyrimidine ring,
wherein the ring system may be substituted by one substituent
selected from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy.
15. The compound of claim 1, wherein the radical R.sup.8 which is
in 3-position of the dihydro-pyridin-ring represents hydrogen, and
the radical R.sup.8 which is in 4-position of the
dihydro-pyridin-ring represents a phenyl, pyridine or pyrimidine
ring, wherein the ring system may be substituted by one substituent
selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl and C.sub.1-6alkoxy.
16. The compound of claim 1, wherein the radical R.sup.8 which is
in 3-position of the dihydro-pyridin-ring represents hydrogen, and
the radical R.sup.8 which is in 4-position of the
dihydro-pyridin-ring represents a phenyl ring which may be
substituted by one substituent selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl and
C.sub.1-6alkoxy.
17. The compound of claim 1, which is selected from:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone,
6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[2,4']bipyrid-
inyl-1'-yl)-methanone,
6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-phenyl-3,6-dihydro-2H-pyridin-1-
-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[2,4']bipyridi-
nyl-1'-yl)-methanone
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[3,4']bipyrid-
inyl-1'-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[3,4']bipyridi-
nyl-1'-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4']bipyridiny-
l-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4']bipyridinyl-
-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl-
-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridiny-
l-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl-
-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridiny-
l-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5',6'-dihydro-2'H-[2,3']bipyridi-
nyl-1'-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5',6'-dihydro-2'H-[2,3']bipyrid-
inyl-1'-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-thiophen-2-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-3,6-dihydro-2H-pyr-
idin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-pyrrol-2-yl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-5-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2'-methyl-3',6'-dihydro-2'H-[2,-
4']bipyridinyl-1'-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2'-methyl-3',6'-dihydro-2'H-[3,-
4']bipyridinyl-1'-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-3,6-dihydro-2H-[4,4']b-
ipyridinyl-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-thiophen-2-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-2-methyl-3,6-dihyd-
ro-2H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-pyrrol-2-yl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methaone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methaone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methaone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone,
[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone,
[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone,
[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyraz-
olo[1,5-a]pyrimidin-2-yl)-methanone,
[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyraz-
olo[1,5-a]pyrimidin-2-yl)-methanone,
[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyraz-
olo[1,5-a]pyrimidin-2-yl)-methanone,
[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone,
[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone,
[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone,
[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone,
[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone,
[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-p-
henyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-p-
henyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-p-
henyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3-
,6-dihydro-2H-pyridin-1-yl]-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydr-
o-2H-pyridin-1-yl]-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-d-
ihydro-2H-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-d-
ihydro-2H-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro--
2H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro--
2H-pyridin-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro--
2H-pyridin-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone,
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridi-
n-1-yl)-methanone,
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridi-
n-1-yl)-methanone and
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridi-
n-1-yl)-methanone.
18. A method for treating or preventing a condition or disease
associated with abnormal glutamate neurotransmission, or a method
for modulating mGluR5 receptors to achieve therapeutic benefit,
such method comprising the step of administering to a living
animal, including a human, a therapeutically effective amount of a
compound of claim 1.
19. The method of claim 18, wherein the condition associated with
abnormal glutamate transmission, or wherein modulation of mGluR5
receptors results in therapeutic benefit is selected from:
Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine
spongiform encephalopathy (BSE), prion related infections, diseases
involving mitochondrial dysfunction, diseases involving
.beta.-amyloid and/or tauopathy, Down's syndrome, hepatic
encephalopathy, Huntington's disease, motor neuron diseases,
amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy,
post-operative cognitive deficit (POCD), systemic lupus
erythematosus, systemic clerosis, Sjogren's syndrome, Neuronal
Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias,
Parkinson's disease, Parkinson's dementia, mild cognitive
impairment, cognitive deficits in various forms of mild cognitive
impairment, cognitive deficits in various forms of dementia,
dementia pugilistica, vascular and frontal lobe dementia, cognitive
impairment, learning impairment, eye injuries, eye diseases, eye
disorders, glaucoma, retinopathy, macular degeneration, head or
brain or spinal cord injuries, head or brain or spinal cord trauma,
trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia,
ischaemia resulting from cardiac arrest or stroke or bypass
operations or transplants, convulsions, epileptic convulsions,
epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear
insult, inner ear insult in tinnitus, tinnitus, sound- or
drug-induced inner ear insult, sound- or drug-induced tinnitus,
L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's
disease therapy, dyskinesias, dyskinesia in Huntington's disease,
drug induced dyskinesias, neuroleptic-induced dyskinesias,
haloperidol-induced dyskinesias, dopaminomimetic-induced
dyskinesias, chorea, Huntington's chorea, athetosis, dystonia,
stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis
spasmodicus, blepharospasm, focal and generalized dystonia,
nystagmus, hereditary cerebellar ataxias, corticobasal
degeneration, tremor, essential tremor, abuse, addiction, nicotine
addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate
addiction, opiate abuse, cocaine addiction, cocaine abuse,
amphetamine addiction, amphetamine abuse, anxiety disorders, panic
disorders, anxiety and panic disorders, social anxiety disorder
(SAD), attention deficit hyperactivity disorder (ADHD), attention
deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity
in children, autism, dementia, dementia in Alzheimer's disease,
dementia in Korsakoff syndrome, Korsakoff syndrome, vascular
dementia, dementia related to HIV infections, HIV-1 encephalopathy,
AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia,
major depressive disorder, major depression, depression, depression
resulting from Borna virus infection, major depression resulting
from Borna virus infection, bipolar manic-depressive disorder, drug
tolerance, drug tolerance to opioids, movement disorders, fragile-X
syndrome, irritable bowel syndrome (IBS), migraine, multiple
sclerosis (MS), muscle spasms, pain, chronic pain, acute pain,
inflammatory pain, neuropathic pain, diabetic neuropathic pain
(DNP), pain related to rheumatic arthritis, allodynia,
hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress
disorder (PTSD), schizophrenia, positive or cognitive or negative
symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary
incontinence, vomiting, pruritic conditions, pruritis, sleep
disorders, micturition disorders, neuromuscular disorder in the
lower urinary tract, gastroesophageal reflux disease (GERD),
gastrointestinal dysfunction, lower esophageal sphincter (LES)
disease, functional gastrointestinal disorders, dyspepsia,
regurgitation, respiratory tract infection, bulimia nervosa,
chronic laryngitis, asthma, reflux-related asthma, lung disease,
eating disorders, obesity, obesity-related disorders, obesity
abuse, food addiction, binge eating disorders, agoraphobia,
generalized anxiety disorder, obsessive-compulsive disorder, panic
disorder, posttraumatic stress disorder, social phobia, phobic
disorders, substance-induced anxiety disorder, delusional disorder,
schizoaffective disorder, schizophreniform disorder,
substance-induced psychotic disorder, or delirium; inhibition of
tumour cell growth, migration, invasion, adhesion and toxicity in
the peripheral tissues, peripheral nervous system and CNS;
neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral
cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma
(SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate
cancer, gastric cancer, liver cancer, colon cancer, colorectal
carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve
tissue, glioma, malignant glioma, astroglioma, neuroglioma,
neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells,
melanoma, malignant melanoma, epithelial neoplasm, lymphoma,
myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma,
and other tumours.
20. The method of claim 18, wherein the condition associated with
abnormal glutamate transmission, or wherein modulation of mGluR5
receptors results in therapeutic benefit is selected from: chronic
pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer
pain, pain related to rheumathic arthritis, inflammatory pain,
L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias,
L-dopa-induced dyskinesias in Parkinson's disease therapy,
dopaminomimetic-induced dyskinesias in Parkinson's disease therapy,
tardive dyskinesias, Parkinson's disease, anxiety disorders, panic
disorders, anxiety and panic disorders, social anxiety disorder
(SAD), generalized anxiety disorder, substance-induced anxiety
disorder, eating disorders, obesity, binge eating disorders,
Huntington's chorea, epilepsy, Alzheimer's disease, positive and
negative symptoms of schizophrenia, cognitive impairment,
functional gastrointestinal disorders, gastroesophageal reflux
disease (GERD), migraine, irritable bowel syndrome (IBS), or for
cognitive enhancement and/or neuroprotection.
21. The method of claim 18, wherein the condition associated with
abnormal glutamate transmission, or wherein modulation of mGluR5
receptors results in therapeutic benefit is selected from: chronic
pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer
pain, pain related to rheumathic arthritis, inflammatory pain,
L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias,
L-dopa-induced dyskinesias in Parkinson's disease therapy,
dopaminomimetic-induced dyskinesias in Parkinson's disease therapy,
tardive dyskinesias, Parkinson's disease, anxiety disorders, panic
disorders, anxiety and panic disorders, social anxiety disorder
(SAD), generalized anxiety disorder, substance-induced anxiety
disorder, eating disorders, obesity, binge eating disorders,
migraine, irritable bowel syndrome (IBS), functional
gastrointestinal disorders, gastroesophageal reflux disease (GERD),
Huntington's chorea and epilepsy.
22. The method of claim 18, wherein the condition associated with
abnormal glutamate transmission, or wherein modulation of mGluR5
receptors results in therapeutic benefit is selected from:
Alzheimer's disease, positive and/or negative symptoms of
schizophrenia, cognitive impairment, or cognitive enhancement and
neuroprotection.
23. The method of claim 18, wherein the condition associated with
abnormal glutamate transmission, or wherein modulation of mGluR5
receptors results in therapeutic benefit, is a binge eating
disorder.
24. A pharmaceutical composition comprising as active ingredient at
least one compound of claim 1 together with one or more
pharmaceutically acceptable excipients.
25. A pharmaceutical composition comprising a combination of at
least one compound of claim 1 and at least one NMDA receptor
antagonist, together with one or more pharmaceutically acceptable
excipients.
26. A process for the synthesis of a compound selected from those
of formula (I) ##STR162## wherein R.sup.1 represents chloro or
bromo; R.sup.2 and R.sup.3 each independently represent hydrogen,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.2
and R.sup.3 both together with the carbon atom of the ring
represent a carbonyl group; R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or R.sup.4 and R.sup.5 both together with the
carbon atom of the ring represent a carbonyl group; R.sup.6 and
R.sup.7 independently represent hydrogen, C.sub.1-6-alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.6 and R.sup.7 both
together with the carbon atom of the ring represent a carbonyl
group; R.sup.2 or R.sup.3 together with R.sup.6 and R.sup.7 may
also form a bivalent radical selected from the group
CH.sub.2--CH.sub.2 and CH.sub.2--O; R.sup.8 represents a radical
R.sup.9 or a radical R.sup.10, whereby one of the two radicals
R.sup.8 represents R.sup.9 and the other radical R.sup.8 represents
R.sup.10; R.sup.9 represents an aryl, heteroaryl or heterocycle,
wherein the ring system may be optionally substituted by one or two
substituents, which may be the same or different and selected
independently from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; R.sup.10 represents
hydrogen or C.sub.1-6alkyl; and optical isomers, pharmaceutically
acceptable salts, hydrates, solvates, and polymorphs thereof,
wherein a compound of formula (II) ##STR163## is suspended in a
mixture of ethanol and water and treated with hydrochloric acid,
followed by reaction with H.sub.2NNHCOOCH.sub.3 to yield a compound
of Formula (III) ##STR164## which is reacted with a compound of
Formula (IV) ##STR165## to yield a compound of Formula (V)
##STR166## which is hydrolyzed under acidic conditions to yield a
compound of Formula (VI) ##STR167## which is treated with an amine
of Formula (VII) ##STR168## in the presence of a condensing agent,
to yield a compound of Formula (I), which is converted, if desired,
to a pharmaceutically acceptable salt, hydrate, solvate, or
polymorph.
27. A compound selected from those of formula (VII) ##STR169##
wherein R.sup.2 and R.sup.3 each independently represent hydrogen,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.2
and R.sup.3 both together with the carbon atom of the ring
represent a carbonyl group; R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or R.sup.4 and R.sup.5 both together with the
carbon atom of the ring represent a carbonyl group; R.sup.6 and
R.sup.7 independently represent hydrogen, C.sub.1-6-alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.6 and R.sup.7 both
together with the carbon atom of the ring represent a carbonyl
group; R.sup.2 or R.sup.3 together with R.sup.6 and R.sup.7 may
also form a bivalent radical selected from the group
CH.sub.2--CH.sub.2 and CH.sub.2--O; R.sup.8 represents a radical
R.sup.9 or a radical R.sup.10, whereby one of the two radicals
R.sup.8 represents R.sup.9 and the other radical R.sup.8 represents
R.sup.10; R.sup.9 represents a cyclic group selected from aryl,
heteroaryl or heterocyclyl, wherein the ring system may be
optionally substituted by one or two substituents, which may be the
same or different and selected independently from halogen, amino,
hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; R.sup.10
represents hydrogen or C.sub.1-6alkyl.
28. A process for the synthesis of a compound selected from those
of formula (I) ##STR170## wherein R.sup.1 represents chloro or
bromo; R.sup.2 and R.sup.3 each independently represent hydrogen,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.2
and R.sup.3 both together with the carbon atom of the ring
represent a carbonyl group; R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or R.sup.4 and R.sup.5 both together with the
carbon atom of the ring represent a carbonyl group; R.sup.6 and
R.sup.7 independently represent hydrogen, C.sub.1-6-alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or R.sup.6 and R.sup.7 both
together with the carbon atom of the ring represent a carbonyl
group; R.sup.2 or R.sup.3 together with R.sup.6 and R.sup.7 may
also form a bivalent radical selected from the group
CH.sub.2--CH.sub.2 and CH.sub.2--O; R.sup.8 represents a radical
R.sup.9 or a radical R.sup.10, whereby one of the two radicals
R.sup.8 represents R.sup.9 and the other radical R.sup.8 represents
R.sup.10; R.sup.9 represents a cyclic group selected from aryl,
heteroaryl or heterocyclyl, wherein the ring system may be
optionally substituted by one or two substituents, which may be the
same or different and selected independently from halogen, amino,
hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; R.sup.10
represents hydrogen or C.sub.1-6alkyl; and optical isomers,
pharmaceutically acceptable salts, hydrates, solvates, and
polymorphs thereof, wherein a compound of Formula (VIII) ##STR171##
is dissolved in an alcoholic solvent and treated with thionyl
chloride to yield a compound of Formula IX ##STR172## wherein PG
represents C.sub.1-6alkyl, which is reduced under standard
conditions to yield a compound of Formula X ##STR173## which is
reacted with a compound of Formula (IV) ##STR174## to yield a
compound of Formula (XI) ##STR175## which is hydrolyzed under
acidic conditions to yield a compound of Formula (VI) ##STR176##
which is treated with an amine of Formula (VII) ##STR177## in the
presence of a condensing agent, to yield a compound of Formula (I),
which is converted, if desired, to a pharmaceutically acceptable
salt, hydrate, solvate, or polymorph.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pyrazolopyrimidine
derivatives, which can act as novel metabotropic glutamate receptor
(mGluR) modulators, methods for their synthesis and their use as a
medicament for the treatment of various diseases and/or prevention
of disorders, e.g. neurological disorders, by administration of
such substances.
BACKGROUND OF THE INVENTION
[0002] Neuronal stimuli are transmitted by the central nervous
system (CNS) through the interaction of a neurotransmitter released
by a neuron, which neurotransmitter has a specific effect on a
neuroreceptor of another neuron. L-glutamic acid is considered to
be a major excitatory neurotransmitter in the mammalian CNS,
consequently playing a critical role in a large number of
physiological processes. Glutamate-dependent stimulus receptors are
divided into two main groups. The first group comprises
ligand-controlled ion channels whereas the other comprises
metabotropic glutamate receptors (mGluR). Metabotropic glutamate
receptors are a subfamily of G-protein-coupled receptors (GPCR).
There is increasing evidence for a peripheral role of both
ionotropic and metabotropic glutamate receptors outside the CNS
e.g., in chronic pain states.
[0003] At present, eight different members of these mGluRs are
known. On the basis of structural parameters such as sequence
homology, the second messenger system utilized by these receptors
and their different affinity to low-molecular weight compounds,
these eight receptors can be divided into three groups. MGluR1 and
mGluR5 belong to Group I which are positively coupled to
phospholipase C and their activation leads to a mobilization of
intracellular calcium ions. MGluR2 and mGluR3 belong to Group II
and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of
which are negatively coupled to adenylyl cyclase, i.e., their
activation causes a reduction in second messenger cAMP and thus a
dampening of neuronal activity.
[0004] The mGluR5 modulators have been shown to modulate the
effects of the presynaptically released neurotransmitter glutamate
via postsynaptic mechanisms. Moreover, as these modulators can be
both positive and/or negative mGluR5 modulators, such modulators
may increase or inhibit the effects mediated through these
metabotropic glutamate receptors.
[0005] Of particular interest are those modulators which are
negative mGluR5 modulators. Such modulators decrease the effects
mediated through metabotropic glutamate receptors. Since a variety
of patho-physiological processes and disease states affecting the
CNS are thought to be related to abnormal glutamate
neurotransmission, and mGluR5 receptors are shown to be expressed
in several areas of the CNS, modulators of these receptors could be
therapeutically beneficial in the treatment of CNS diseases.
[0006] Therefore, mGluR5 positive or negative modulators may be
administered to provide neuroprotection and/or disease modification
in the following acute or chronic pathological conditions or to
provide a symptomatological effect on the following conditions:
[0007] Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease,
bovine spongiform encephalopathy (BSE), prion related infections,
diseases involving mitochondrial dysfunction, diseases involving
.beta.-amyloid and/or tauopathy, Down's syndrome, hepatic
encephalopathy, Huntington's disease, motor neuron diseases,
amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy,
post-operative cognitive deficit (POCD), systemic lupus
erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal
Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias,
Parkinson's disease, Parkinson's dementia, mild cognitive
impairment, cognitive deficits in various forms of mild cognitive
impairment, cognitive deficits in various forms of dementia,
dementia pugilistica, vascular and frontal lobe dementia, cognitive
impairment, learning impairment, eye injuries, eye diseases, eye
disorders, glaucoma, retinopathy, macular degeneration, head or
brain or spinal cord injuries, head or brain or spinal cord trauma,
trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia,
ischaemia resulting from cardiac arrest or stroke or bypass
operations or transplants, convulsions, epileptic convulsions,
epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear
insult, inner ear insult in tinnitus, tinnitus, sound- or
drug-induced inner ear insult, sound- or drug-induced tinnitus,
L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's
disease therapy, dyskinesias, dyskinesia in Huntington's disease,
drug induced dyskinesias, neuroleptic-induced dyskinesias,
haloperidol-induced dyskinesias, dopaminomimetic-induced
dyskinesias, chorea, Huntington's chorea, athetosis; dystonia,
stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis
spasmodicus, blepharospasm, focal and generalized dystonia,
nystagmus, hereditary cerebellar ataxias, corticobasal
degeneration, tremor, essential tremor, abuse, addiction, nicotine
addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate
addiction, opiate abuse, cocaine addiction, cocaine abuse,
amphetamine addiction, amphetamine abuse, anxiety disorders, panic
disorders, anxiety and panic disorders, social anxiety disorder
(SAD), attention deficit hyperactivity disorder (ADHD), attention
deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity
in children, autism, dementia, dementia in Alzheimer's disease,
dementia in Korsakoff syndrome, Korsakoff syndrome, vascular
dementia, dementia related to HIV infections, HIV-1 encephalopathy,
AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia,
major depressive disorder, major depression, depression, depression
resulting from Borna virus infection, major depression resulting
from Borna virus infection, bipolar manic-depressive disorder, drug
tolerance, drug tolerance to opioids, movement disorders, fragile-X
syndrome, irritable bowel syndrome (IBS), migraine, multiple
sclerosis (MS), muscle spasms, pain, chronic pain, acute pain,
inflammatory pain, neuropathic pain, diabetic neuropathic pain
(DNP), pain related to rheumatic arthritis, allodynia,
hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress
disorder (PTSD), schizophrenia, positive or cognitive or negative
symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary
incontinence, vomiting, pruritic conditions, pruritis, sleep
disorders, micturition disorders, neuromuscular disorder in the
lower urinary tract, gastroesophageal reflux disease (GERD),
gastrointestinal dysfunction, lower esophageal sphincter (LES)
disease, functional gastrointestinal disorders, dyspepsia,
regurgitation, respiratory tract infection, bulimia nervosa,
chronic laryngitis, asthma, reflux-related asthma, lung disease,
eating disorders, obesity, obesity-related disorders, obesity
abuse, food addiction, binge eating disorders, agoraphobia,
generalized anxiety disorder, obsessive-compulsive disorder, panic
disorder, posttraumatic stress disorder, social phobia, phobic
disorders, substance-induced anxiety disorder, delusional disorder,
schizoaffective disorder, schizophreniform disorder,
substance-induced psychotic disorder, or delirium.
[0008] The mGluR5 negative or positive modulators may also be
administered to provide inhibition of tumour cell growth,
migration, invasion, adhesion and toxicity in the peripheral
tissues, peripheral nervous system and CNS. MGluR5 modulators may
be administered to provide therapeutic intervention in neoplasia,
hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer,
squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC),
lung cancer, lung adenocarcinoma, breast cancer, prostate cancer,
gastric cancer, liver cancer, colon cancer, colorectal carcinoma,
rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma,
malignant glioma, astroglioma, neuroglioma, neuroblastoma,
glioblastoma, medulloblastoma, cancer of skin cells, melanoma,
malignant melanoma, epithelial neoplasm, lymphoma, myeloma,
Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, and other
tumours.
[0009] Further indications for mGluR5 negative or positive
modulators include those indications wherein a particular condition
does not necessarily exist but wherein a particular physiological
parameter may be improved through administration of the instant
compounds, for example cognitive enhancement, learning impairment
and/or neuroprotection.
[0010] Positive modulators may be particularly useful in the
treatment of positive and negative symptoms in schizophrenia and
cognitive deficits in various forms of dementia and mild cognitive
impairment.
[0011] In the literature, several types of modulators of mGluR5
have already been described.
[0012] Furthermore, several types of pyrazolopyrimidine compounds
have been disclosed in the prior art.
[0013] Various methods for preparing substituted pyrazolopyrimidine
derivatives are known, e.g. from G. Hajos and Z. Riedl, Science of
Synthesis 109, 613-678 (2002) and from Laura Bettinetti (Ph. D.
Thesis, University of Erlangen, Germany, 2004).
[0014] In WO 2004/087153 various pyrazolopyrimidines of formula
(XXII) are described, which can act as small molecule immune
potentiators (SMIP) and which can be used e.g. for cancer
treatment. ##STR2##
[0015] Furthermore, in WO 2004/089471, the use of substituted
pyrazolo[1,5-a]pyrimidines or prodrugs or salts thereof are
described for the preparation of a pharmaceutical composition for
the treatment of disorders and diseases where it is desirable to
modulate the activity of the enzyme 11.beta.HSD1 or to inhibit
11.beta.HSD1. In the document WO 2004/089471,
pyrazolo(1,5-a)pyrimidine derivates of the following general
formula (C) are disclosed: ##STR3##
[0016] In WO 2003/037900, further specific pyrazolopyrimidine
compounds are described as inhibitors of ion-channels in human
cells. In this document compounds having the following general
formula (X) are described: ##STR4## [0017] wherein [0018] R.sup.1
is e.g. alkyl; R.sup.2 is a e.g. hydrogen or alkyl; or [0019]
R.sup.1 and R.sup.2 taken together with the nitrogen atom to which
they are optionally joined to form a 4- to 8-membered
heterocycloaryl ring; [0020] R.sup.3 is e.g. hydrogen, alkyl, halo,
amino or aryl; [0021] R.sup.4 is e.g. hydrogen, halo, alkyl or
aryl; and [0022] R.sup.5 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted
or unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl; R.sup.6 is e.g. hydrogen, halo or aryl; and
[0023] X is a member selected from O and S.
[0024] Several pyrazolopyrimidine compounds according to the
present invention, however have been tested which are found to be
not significantly active as inhibitors of ion-channels in human
cells. In this document WO 2003/037900, compounds of the following
two structures are mentioned as example compounds (B308) and
(B310), which however have shown no particular activity as
metabotropic glutamate receptor (mGluR5) modulators: ##STR5##
(6-Bromopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone
[0025] ##STR6##
(6-Bromopyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone
[0026] In WO 2003/101993 several types of pyrazolopyrimidine
compounds and their use for the treatment of hepatitis infections
are disclosed. WO 2003/101993 deals with compounds of the following
general formula (Z) ##STR7## [0027] wherein: [0028] G.sup.1 is
selected e.g. from the group of --OH, cyano, --C(O)--OH,
--C(O)--NR.sup.2R.sup.3, where R.sup.2 and R.sup.3 taken together
from a 5- or 6-membered heteroaromatic or saturated or partially
unsaturated heterocyclic ring, or [0029] G.sup.2 is independently
are selected from the group consisting e.g. of alkyl, cycloalkyl,
aryl, heteroaryl, saturated or partially unsaturated heterocyclic
radical, trifluoromethyl, [0030] G.sup.3 can be absent or is
independently selected from the group consisting of e.g. alkyl,
cycloalkyl, aryl, heteroaryl, saturated or partially unsaturated
heterocyclic radical, [0031] G.sup.2 and G.sup.3, collectively, are
attached at any two of positions C7, C8 and C9 of the pyrimidine
ring, the remaining position being optionally substituted with
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, hydroxyl, alkoxy, or
cyano; [0032] wherein the ring portion of any of said cycloalkyl,
aryl, aralkyl, heteroaryl, heteroarylalkyl, or heterocyclic radical
in G.sup.1, G.sup.2 or G.sup.3 can be optionally substituted.
[0033] In the document WO 2003/091256 particular pyrazolopyrimidine
derivatives which have a NADPH-oxidase inhibitor activity are
described. The compounds have the following general formula (Y)
##STR8## [0034] wherein R.sub.1a, R.sub.2a, R.sub.3-R.sub.5
represent hydrogen, halogen, lower alkyl that may be substituted,
lower alkenyl that may be substituted, lower alkynyl that may be
substituted, cycloalkyl that may be substituted, cycloalkenyl that
may be substituted, cycloalkynyl that may be substituted, aryl that
may be substituted, heterocyclic group that may be substituted,
hydroxyl, alkoxy that may be substituted, aryloxy that may be
substituted, heterocyclic oxy that may be substituted, acyl that
may be substituted, monosubstituted carbonyloxy that may be
substituted, carbamoyl that may be substituted, diazo, amidino that
may be substituted, azido, nitroso, nitro, amino that may be
substituted, imino that may be substituted, cyano, mercapto,
monosubstituted sulfinyl that may be substituted, monosubstituted
sulfonyl that may be substituted, sulfo, or trisubstituted silyl,
and any combinations of R.sub.1a, R.sub.2a, R.sub.3-R.sub.5 may
together form a ring structure.
[0035] A further pyrazolopyrimidine compound which has already been
described in the literature (see ChemBridge Corporation; Registry
Nr. 833441-66-0; of Feb. 18, 2005), has the following structure
(M): ##STR9##
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,2,3,4-tetrahydro-isoquinolin-2--
yl)-methanon
[0036] This compound, however has only a limited activity as
metabotropic glutamate receptor (mGluR5) modulator and furthermore
is not selective.
[0037] In WO 2006/015737 further heterocyclic compounds which can
contain a carboxylic acid amid function are disclosed which have an
activity at dopamine receptors and which can be used for the
treatment of CNS-diseases. As one example structure,
pyrazolopyrimidines are mentioned.
[0038] In WO 2002/088088 the synthesis of tetrahydro-isoquinolin
compounds is disclosed which can serve as intermediates for the
synthesis of pharmaceutically active compounds.
THE PRESENT INVENTION
[0039] It now has been found that certain pyrazolopyrimidine
derivatives which differ in structure from the known
pyrazolopyrimidines, are potent mGluR5 modulators. Therefore, these
substances may be therapeutically beneficial in the treatment of
conditions which involve abnormal glutamate neurotransmission or in
which modulation of mGluR5 receptors results in therapeutic
benefit. These substances are preferably administered in the form
of a pharmaceutical composition, wherein they are present together
with one or more pharmaceutically acceptable diluents, carriers, or
excipients.
OBJECTS OF THE INVENTION
[0040] It is an object of the present invention to provide novel
pharmaceutical compounds which are mGluR5 modulators and
pharmaceutical compositions thereof. It is a further object of the
invention to provide a novel method of treating, eliminating,
alleviating, palliating, or ameliorating undesirable CNS disorders
which involve abnormal glutamate neurotransmission by employing a
compound of the invention or a pharmaceutical composition
containing the same.
[0041] An additional object of the invention is the provision of
processes for producing the pyrazolopyrimidine derivatives.
SUMMARY OF THE INVENTION
[0042] The invention in general deals with: A compound selected
from those of formula (Ig) ##STR10## [0043] wherein [0044] R.sup.1
represents chloro or bromo; [0045] R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7, which may be the same or different,
each independently represent hydrogen, C.sub.1-6alkyl, amino,
hydroxy, halogen, or trifluoromethyl; [0046] R.sup.8 represents
hydrogen, or C.sub.1-6alkyl; [0047] R.sup.9 represents aryl or
heteroaryl, wherein the aryl or heteroaryl group may be optionally
substituted by one or more substituents (e.g., 1, 2, or 3), which
may be the same or different, selected independently from halogen,
amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy,
aminocarbonyl, N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0048] or
R.sup.8 and R.sup.9 together with the carbon atoms to which they
are attached may form an unsaturated cyclic ring system containing
5 to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1, 2,
3 or 4) of the carbon atoms of the ring system formed by R.sup.8
and R.sup.9 may be replaced by heteroatoms independently selected
from nitrogen, oxygen and sulfur and wherein the ring system may be
optionally substituted by one or more (e.g., 1, 2, or 3)
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0049] and
optical isomers, pharmaceutically acceptable salts, hydrates,
solvates, and polymorphs thereof; it being understood that: the
compound of Formula Ig does not represent:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-
-methanone.
[0050] Furthermore, a compound of Formula (Ig), wherein [0051]
R.sup.8 represents hydrogen or methyl; [0052] R.sup.1 represents
chloro or bromo; [0053] R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7, which may be the same or different, each independently
represent hydrogen, C.sub.1-6alkyl, amino, hydroxy, halogen, or
trifluoromethyl; [0054] R.sup.9 represents aryl or heteroaryl,
wherein the aryl or heteroaryl group may be optionally substituted
by one or more substituents (e.g., 1, 2, or 3), which may be the
same or different, selected independently from halogen, amino,
hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy,
aminocarbonyl, N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0055] or
R.sup.8 and R.sup.9 together with the carbon atoms to which they
are attached may form an unsaturated cyclic ring system containing
5 to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1, 2,
3 or 4) of the carbon atoms of the ring system formed by R.sup.8
and R.sup.9 may be replaced by heteroatoms independently selected
from nitrogen, oxygen and sulfur and wherein the ring system may be
optionally substituted by one or more (e.g., 1, 2, or 3)
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl.
[0056] Such a compound of Formula (Ig), wherein [0057] R.sup.9
represents phenyl or monocyclic heteroaryl, wherein the heteroaryl
ring contains from 1 to 4 (i.e. 1, 2, 3 or 4) heteroatoms selected
independently from oxygen, sulfur and nitrogen and wherein the
phenyl or heteroaryl ring may be optionally substituted by one to
three substituents, which may be the same or different, selected
independently from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0058] R.sup.1
represents chloro or bromo; [0059] R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7, which may be the same or different,
each independently represent hydrogen, C.sub.1-6alkyl, amino,
hydroxy, halogen, or trifluoromethyl; and [0060] R.sup.8 represents
hydrogen, or methyl.
[0061] Such a compound of Formula (Ig), wherein [0062] R.sup.8
represents hydrogen; [0063] R.sup.9 represents phenyl, optionally
substituted by one to two substituents, which may be the same or
different, selected independently from halogen, amino, hydroxy,
nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy, and
C.sub.1-6alkylcarbonylamino; [0064] R.sup.1 represents chloro or
bromo; and [0065] R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7, which may be the same or different, each independently
represent hydrogen, C.sub.1-6alkyl, amino, hydroxy, halogen, or
trifluoromethyl.
[0066] Such a compound of Formula (Ig), wherein [0067] R.sup.8
represents hydrogen; [0068] R.sup.9 represents phenyl, optionally
substituted by one to two substituents, which may be the same or
different, selected independently from halogen, amino, hydroxy,
nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy, and
C.sub.1-6alkylcarbonylamino; [0069] R.sup.1 represents chloro or
bromo; [0070] R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which may be
the same or different, each independently represent hydrogen or
methyl; and [0071] R.sup.6 and R.sup.7 represent hydrogen.
[0072] Such a compound of Formula (Ig), wherein [0073] R.sup.8
represents hydrogen; [0074] R.sup.9 represents phenyl, optionally
substituted by one to two substituents, which may be the same or
different, selected independently from halogen, amino, hydroxy,
nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy, and
C.sub.1-6alkylcarbonylamino; [0075] R.sup.1 represents chloro or
bromo; [0076] R.sup.6 and R.sup.7 represent hydrogen; and [0077]
one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represents methyl and
the remaining of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represent
hydrogen.
[0078] Such a compound of Formula (Ig), wherein [0079] R.sup.8 and
R.sup.9 together with the carbon atoms to which they are attached
form an unsaturated cyclic ring system containing 6 carbon atoms,
wherein 0 to 2 (i.e. 0, 1 or 2) of the carbon atoms of the ring
system formed by R.sup.8 and R.sup.9, may be replaced by a
heteroatom independently selected from nitrogen, oxygen and sulfur
and wherein the ring system may be optionally substituted by one or
more (e.g., 1, 2, or 3) substituents, which may be the same or
different, independently selected from halogen, amino, hydroxy,
nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0080] R.sup.1
represents chloro or bromo; and [0081] R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7, which may be the same or different,
each independently represent hydrogen, C.sub.1-6alkyl, amino,
hydroxy, halogen, or trifluoromethyl.
[0082] Such compound of Formula (Ig), wherein [0083] R.sup.8 and
R.sup.9 together with the carbon atoms to which they are attached
form a benzene ring system optionally substituted by one to two
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy and
C.sub.1-6alkylcarbonylamino; [0084] R.sup.1 represents chloro or
bromo; and [0085] R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7, which may be the same or different, each independently
represent hydrogen, C.sub.1-6alkyl, amino, hydroxy, halogen, or
trifluoromethyl.
[0086] Such compound of Formula (Ig), wherein [0087] R.sup.8 and
R.sup.9 together with the carbon atoms to which they are attached
form a benzene ring system optionally substituted by one to two
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy and
C.sub.1-6alkylcarbonylamino; [0088] R.sup.1 represents chloro or
bromo; [0089] R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which may be
the same or different, independently represent hydrogen or methyl;
and [0090] R.sup.6 and R.sup.7 represent hydrogen.
[0091] Furthermore, a compound of Formula (Ig), wherein [0092]
R.sup.8 and R.sup.9 together with the carbon atoms to which they
are attached form a benzene ring system optionally substituted by
one to two substituents, which may be the same or different,
independently selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy and
C.sub.1-6alkylcarbonylamino; [0093] R.sup.1 represents chloro or
bromo; [0094] R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which may be
the same or different, independently represent hydrogen or ethyl or
trifluoromethyl; and [0095] R.sup.6 and R.sup.7 represent
hydrogen.
[0096] Such compound of Formula (Ig), wherein [0097] R.sup.8 and
R.sup.9 together with the carbon atoms to which they are attached
form a benzene ring system optionally substituted by one to two
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy and
C.sub.1-6alkylcarbonylamino; [0098] R.sup.1 represents chloro or
bromo; [0099] R.sup.6 and R.sup.7 represent hydrogen; and [0100]
one of R.sup.2 and R.sup.3 represents methyl and the remaining of
R.sup.2 and R.sup.3, and R.sup.4 and R.sup.5, represent
hydrogen.
[0101] Furthermore, a compound of Formula (Ig), wherein [0102]
R.sup.8 and R.sup.9 together with the carbon atoms to which they
are attached form a benzene ring system optionally substituted by
one to two substituents, which may be the same or different,
independently selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy and
C.sub.1-6alkylcarbonylamino; [0103] R.sup.1 represents chloro or
bromo; [0104] R.sup.6 and R.sup.7 represent hydrogen; and [0105]
one of R.sup.2 and R.sup.3 represents ethyl or trifluoromethyl and
the remaining of R.sup.2 and R.sup.3, and R.sup.4 and R.sup.5,
represent hydrogen.
[0106] Such a compound of Formula (Ig), wherein [0107] R.sup.8 and
R.sup.9 together with the carbon atoms to which they are attached
form an unsaturated cyclic ring system containing 5 carbon atoms,
wherein 0 to 3 (i.e. 0, 1, 2 or 3) of the carbon atoms of the ring
formed by R.sup.8 and R.sup.9 may be replaced by a heteroatom
independently selected from nitrogen, oxygen and sulfur and wherein
the ring system may be optionally substituted by one to two
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0108] R.sup.1
represents chloro or bromo; and [0109] R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7, which may be the same or different,
each independently represent hydrogen, C.sub.1-6alkyl, amino,
hydroxy, halogen, or trifluoromethyl.
[0110] Such a compound of Formula (Ig), which is selected from
those of Formula (IgA), ##STR11## [0111] wherein [0112] Y
represents NH, S, or O; [0113] R.sup.10 and R.sup.11, which may be
the same or different, each independently represent hydrogen,
halogen, amino, hydroxy, nitro, cyano, trifluoromethyl,
trifluoromethoxy, aminocarbonyl, N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy, or
C.sub.1-6alkylcarbonylamino; [0114] R.sup.1 represents chloro or
bromo; and [0115] R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7, which may be the same or different, each independently
represent hydrogen, C.sub.1-6alkyl, amino, hydroxy, halogen, or
trifluoromethyl.
[0116] Such a compound of Formula (IgA), [0117] wherein Y
represents NH, S, or O; [0118] R.sup.10 and R.sup.11 which may be
the same or different, each independently represent hydrogen,
halogen, amino, hydroxy, nitro, cyano, trifluoromethyl,
trifluoromethoxy, aminocarbonyl, N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy, or
C.sub.1-6alkylcarbonylamino; [0119] R.sup.1 represents chloro or
bromo; [0120] R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which may be
the same or different, independently represent hydrogen or methyl;
and [0121] R.sup.6 and R.sup.7 represent hydrogen.
[0122] Such a compound of Formula (IgA), [0123] wherein Y
represents NH, S, or O; [0124] R.sup.10 and R.sup.11, which may be
the same or different, each independently represent hydrogen,
halogen, amino, hydroxy, nitro, cyano, trifluoromethyl,
trifluoromethoxy, aminocarbonyl, N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylcarbonyloxy, or
C.sub.1-6alkylcarbonylamino; [0125] R.sup.1 represents chloro or
bromo; [0126] R.sup.6 and R.sup.7 represent hydrogen; and [0127]
one of R.sup.2 and R.sup.3 represents methyl and the remaining of
R.sup.2 and R.sup.3, and R.sup.4 and R.sup.5, represent
hydrogen.
[0128] Furthermore, a compound selected from those of Formula (Ig)
##STR12## [0129] wherein [0130] R.sup.1 represents chloro or bromo;
[0131] R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7,
which may be the same or different, each independently represent
hydrogen, C.sub.1-6alkyl, amino, hydroxy, halogen, or
trifluoromethyl; [0132] R.sup.8 represents hydrogen, or
C.sub.1-6alkyl; [0133] R.sup.9 represents aryl or heteroaryl,
wherein the aryl or heteroaryl group may be optionally substituted
by one or more substituents (e.g., 1, 2, or 3), which may be the
same or different, selected independently from halogen, amino,
hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy,
aminocarbonyl, N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; [0134] or
R.sup.8 and R.sup.9 together with the carbon atoms to which they
are attached may form an unsaturated cyclic ring system containing
5 to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1, 2,
3 or 4) of the carbon atoms of the ring system formed by R.sup.8
and R.sup.9 may be replaced by heteroatoms independently selected
from nitrogen, oxygen and sulfur and wherein the ring system may be
optionally substituted by one or more (e.g., 1, 2, or 3)
substituents, which may be the same or different, independently
selected from halogen, amino, hydroxy, nitro, cyano,
trifluoromethyl, trifluoromethoxy, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-C.sub.1-6alkylamino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylenedioxy, aryl,
heteroaryl, heterocyclyl, and cycloC.sub.3-12alkyl; or an optical
isomer, pharmaceutically acceptable salt, hydrate, solvate, or
polymorph thereof for use as a medicament.
[0135] In the compounds of the invention R.sup.1 defined by Formula
(Ig) and Formula (IgA) may represent bromo. Alternatively, R.sup.1
defined by Formula (Ig) and Formula (IgA) may represent chloro. It
will be apparent to those skilled in the art that the invention
also includes optical isomers, pharmaceutically acceptable salts,
hydrates, solvates, and polymorphs of the described compounds.
[0136] Moreover the invention deals with a pharmaceutical
composition comprising, together with one or more pharmaceutically
acceptable excipients or vehicles, at least one compound of formula
(Ig) or of formula (IgA), wherein the substituents are as defined
above, or optical isomers, pharmaceutically acceptable salts,
hydrates, solvates, and polymorphs thereof.
[0137] Moreover, a method for treating or preventing a condition or
disease associated with abnormal glutamate neurotransmission or a
method for modulating mGluR5 receptors to achieve therapeutic
benefit, or a method for enhancing cognition, such method
comprising the step of administering to a living animal, including
a human, a therapeutically effective amount of a compound selected
of those of formula (Ig) or formula (IgA).
[0138] Furthermore, the preparation of and the uses of a compound
of formula (Ig) or formula (IgA) or optical isomers,
pharmaceutically acceptable salts, hydrates, solvates, and
polymorphs thereof or the manufacturing or preparation of a
medicament are part of the invention.
[0139] The invention in particular relates to a compound selected
from those of formula (I) ##STR13## [0140] wherein [0141] R.sup.1
represents chloro or bromo; [0142] R.sup.2 and R.sup.3 each
independently represent hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or [0143] R.sup.2 and
R.sup.3 both together with the carbon atom of the ring represent a
carbonyl group; [0144] R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or [0145] R.sup.4 and R.sup.5 both together with
the carbon atom of the ring represent a carbonyl group; [0146]
R.sup.6 and R.sup.7 independently represent hydrogen,
C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or [0147]
R.sup.6 and R.sup.7 both together with the carbon atom of the ring
represent a carbonyl group; [0148] R.sup.2 or R.sup.3 together with
R.sup.6 and R.sup.7 may also form a bivalent radical selected from
the group CH.sub.2--CH.sub.2 and CH.sub.2--O; [0149] R.sup.8
represents a radical R.sup.9 or a radical R.sup.10, whereby one of
the two radicals R.sup.8 represents R.sup.9 and the other radical
R.sup.8 represents R.sup.10; [0150] R.sup.9 represents a cyclic
group selected from aryl, heteroaryl or heterocyclyl, wherein the
ring system may be optionally substituted by one or two
substituents, which may be the same or different and selected
independently from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; [0151] R.sup.10
represents hydrogen or C.sub.1-6alkyl; [0152] and optical isomers,
pharmaceutically acceptable salts, hydrates, solvates, and
polymorphs thereof.
[0153] Such a compound of formula (I), wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently represent
hydrogen, C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or trifluoromethyl;
and one of the radicals R.sup.8 represents hydrogen or methyl and
the other radical R.sup.8 represents a phenyl, thiophene, pyrrole,
tetrazole, furane, pyridine or pyrimidine ring, wherein the ring
system may be optionally substituted by one substituent selected
from halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl and
C.sub.1-6alkoxy.
[0154] Such a compound of formula (I), wherein
R.sup.1 represents chloro or bromo;
R.sup.2 represents hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl;
R.sup.3 represents hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl;
R.sup.4 represents hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl;
R.sup.5 represents hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl;
R.sup.6 represents hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; and
R.sup.7 represents hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl.
[0155] Such a compound of formula (I), wherein
R.sup.1 represents chloro or bromo;
R.sup.2 represents hydrogen, C.sub.1-6alkyl or trifluoromethyl;
R.sup.3 represents hydrogen, C.sub.1-6alkyl or trifluoromethyl;
R.sup.4 represents hydrogen, C.sub.1-6alkyl or trifluoromethyl;
R.sup.5 represents hydrogen, C.sub.1-6alkyl or trifluoromethyl;
R.sup.6 represents hydrogen, C.sub.1-6alkyl or trifluoromethyl;
and
R.sup.7 represents hydrogen, C.sub.1-6alkyl or trifluoromethyl.
[0156] Such a compound of formula (I), wherein
R.sup.10 is hydrogen.
[0157] Such a compound of formula (I), wherein
R.sup.10 is hydrogen and R.sup.9 is in 4-position of the
tetrahydropyridine-ring and represents a substituted phenyl
ring.
[0158] A further embodiment of the invention relates to compounds
of formula (I), wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 independently represent hydrogen, C.sub.1-6-alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; and one of the radicals
R.sup.8 represents hydrogen or methyl and the other radical R.sup.8
represents a phenyl, thiophene, pyrrole, tetrazole, furan, pyridine
or pyrimidine ring, wherein the ring system may be substituted by
one substituent selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl and
C.sub.1-6alkoxy.
[0159] The invention also relates to a compound of formula (I),
wherein one of the radicals R.sup.8 represents hydrogen and the
other radical R.sup.8 represents a phenyl, thiophene, pyrrole,
tetrazole, furan, pyridine or a pyrimidine ring which may be
optionally substituted by one substituent selected from halogen,
amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy.
[0160] A further embodiment of the invention relates to a compound
of formula (I), wherein one of the radicals R.sup.8 represents
hydrogen and the other radical R.sup.8 represents a phenyl,
thiophene, pyrrole, furan, pyridine or pyrimidine ring.
[0161] A further embodiment of the invention relates to a compound
of formula (I), wherein R.sup.6 and R.sup.7 represent hydrogen.
[0162] A further embodiment of the invention relates to compound of
formula (I), wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5
independently represent hydrogen, methyl, ethyl or trifluoromethyl;
and R.sup.6 and R.sup.7 represent hydrogen or methyl.
[0163] A further embodiment of the invention relates to compound of
formula (I), wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 independently represent hydrogen, methyl or ethyl.
[0164] A further embodiment of the invention relates to compound of
formula (I), wherein R.sup.2 and R.sup.3 independently represent
hydrogen, methyl or ethyl. A further embodiment of the invention
relates to compound of formula (I) wherein R.sup.2 represent methyl
or ethyl and R.sup.3 represent hydrogen and which has at least one
chiral carbon atom.
[0165] A further embodiment of the invention relates to compound of
formula (I), wherein R.sup.2 represent hydrogen or methyl and
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 represent
hydrogen.
[0166] A further embodiment of the invention relates to compound of
formula (I), wherein R.sup.1 represents chloro.
[0167] A further embodiment of the invention relates to compound of
formula (I), wherein R.sup.1 represents bromo.
[0168] A further embodiment of the invention relates to a compound
of formula (I), wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 represent hydrogen.
[0169] A further embodiment of the invention relates to a compound
of formula (I), wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 represent hydrogen, and the radical R.sup.8 which is in
3-position of the dihydro-pyridin-ring system also represents
hydrogen.
[0170] A further embodiment of the invention relates to a compound
of formula (I), wherein the radical R.sup.8 which is in 4-position
of the dihydro-pyridin-ring represents a phenyl, thiophene,
pyrrole, tetrazole, furane, pyridine or pyrimidine ring, wherein
the ring system may be optionally substituted by one substituent
selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl and C.sub.1-6alkoxy.
[0171] A further embodiment of the invention relates to a compound
of formula (I), wherein the radical R.sup.8 which is in 3-position
of the dihydro-pyridin-ring represents hydrogen, and the radical
R.sup.8 which is in 4-position of the dihydro-pyridin-ring
represents a phenyl, thiophene, pyrrole, furane, pyridine or
pyrimidine ring.
[0172] The invention includes compounds of formula (I) selected
from the following compounds (or salts thereof) and having the
following chemical names: [0173]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone [0174]
6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone [0175]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[2,4']bipyrid-
inyl-1'-yl)-methanone [0176]
6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-phenyl-3,6-dihydro-2H-pyridin-1-
-yl)-methanone [0177]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[2,4']bipyridi-
nyl-1'-yl)-methanone [0178]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[3,4']bipyrid-
inyl-1'-yl)-methanone [0179]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[3,4']bipyridi-
nyl-1'-yl)-methanone [0180]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4']bipyridiny-
l-1-yl)-methanone [0181]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4']bipyridinyl-
-1-yl)-methanone [0182]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl-
-1-yl)-methanone [0183]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridiny-
l-1-yl)-methanone [0184]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl-
-1-yl)-methanone [0185]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridiny-
l-1-yl)-methanone [0186]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5',6'-dihydro-2'H-[2,3']bipyridi-
nyl-1'-yl)-methanone [0187]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5',6'-dihydro-2'H-[2,3']bipyrid-
inyl-1'-yl)-methanone [0188]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-thiophen-2-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone [0189]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-3,6-dihydro-2H-pyr-
idin-1-yl)-methanone [0190]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-pyrrol-2-yl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0191]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0192]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone [0193]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-21-
H-pyridin-1-yl)-methanone [0194]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-5-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone [0195]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone [0196]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2'-methyl-3',6'-dihydro-2'H-[2,-
4']bipyridinyl-1'-yl)-methanone [0197]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2'-methyl-3',6'-dihydro-2'H-[3,-
4']bipyridinyl-1'-yl)-methanone [0198]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-3,6-dihydro-2H-[4,4']b-
ipyridinyl-1-yl)-methanone [0199]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-thiophen-2-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone [0200]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-2-methyl-3,6-dihyd-
ro-2H-pyridin-1-yl)-methanone [0201]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-pyrrol-2-yl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0202]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone [0203]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone [0204]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone [0205]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0206]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone [0207]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone [0208]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methaone [0209]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methaone [0210]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone [0211]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone [0212]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone [0213]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0214]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0215]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0216]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0217]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H pyridin-1-yl]-methanone [0218]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0219]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0220]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0221]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0222]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0223]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0224]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0225]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0226]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0227]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0228]
[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone [0229]
[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone [0230]
[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone [0231]
[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyraz-
olo[1,5-a]pyrimidin-2-yl)-methanone [0232]
[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyraz-
olo[1,5-a]pyrimidin-2-yl)-methanone [0233]
[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyraz-
olo[1,5-a]pyrimidin-2-yl)-methanone [0234]
[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone [0235]
[4-(3-Bromo-phenyl)-3,6-dihydro-21H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone [0236]
[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone [0237]
[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone [0238]
[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone [0239]
[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a-
]pyrimidin-2-yl)-methanone [0240]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0241] 5
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0242]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0243]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0244]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0245]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0246]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0247]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0248]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone [0249]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0250]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0251]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0252]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone [0253]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone [0254]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone [0255]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-p-
henyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone [0256]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-p-
henyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone [0257]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-p-
henyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone [0258]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0259]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0260]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone [0261]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0262]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0263]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0264]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone [0265]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3-
,6-dihydro-2H-pyridin-1-yl]-methanone [0266]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone [0267]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydr-
o-2H-pyridin-1-yl]-methanone [0268]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-d-
ihydro-2H-pyridin-1-yl)-methanone [0269]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone [0270]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone [0271]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone [0272]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-d-
ihydro-2H-pyridin-1-yl)-methanone [0273]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone [0274]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone [0275]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone [0276]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone [0277]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone [0278]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone [0279]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro--
2H-pyridin-1-yl)-methanone [0280]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro--
2H-pyridin-1-yl)-methanone [0281]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro--
2H-pyridin-1-yl)-methanone [0282]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone [0283]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone [0284]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone [0285]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridi-
n-1-yl)-methanone [0286]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridi-
n-1-yl)-methanone [0287]
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridi-
n-1-yl)-methanone and optical isomers, polymorphs and
pharmaceutically-acceptable acid and base addition salts, hydrates,
and solvates thereof.
[0288] The invention also relates to compounds of the formula (I)
which are marked by radioactive atoms. Typical compounds include
those where one or more hydrogens are substituted by tritium, where
one or more C.sup.12 are substituted by C.sup.14, where one or more
fluor atoms are substituted by F.sup.18 or other isotopes. These
can be used for the treatment of diseases (e.g. cancer) but also
for diagnostic purposes. The radioactive atoms exchanged in the
molecule are often isotopes of carbon, hydrogen, halogen, sulphur
or phosphor.
[0289] Moreover, the invention in general relates to the use of a
metabotropic glutamate receptor modulator (and in particular of a
mGluR5 modulator) for the preparation of a medicament and for the
treatment of various diseases as mentioned hereunder in a mammal,
including humans.
[0290] In particular, the invention relates to the use of a
compound of formula (I) or of formula (Ia) as defined above or an
optical isomer, pharmaceutically acceptable salt, hydrate, solvate
or polymorph thereof for the preparation of a medicament and for
the treatment of a mammal, including humans.
[0291] Further, the invention relates to the use of a compound for
the preparation of a medicament for treating or preventing a
condition or disease associated with abnormal glutamate
neurotransmission. Such a use includes the use of a compound for
the preparation of a medicament for the prevention and/or treatment
of a condition or disease in an animal including a human being
which condition or disease is affected or facilitated by the
negative modulatory effect of mGluR5 modulators.
[0292] The invention is dealing with the use of a mGluR5 modulator
and in particular a compound according to formula (I), for the
preparation of a medicament, including for the conditions or
diseases selected from those mentioned earlier in the
description.
[0293] The invention also relates to the use of a mGluR5 modulator,
in particular a compound according to formula (I), wherein the
condition associated with abnormal glutamate neurotransmission is
selected from those mentioned earlier in the description.
[0294] Further, the invention to the use of a compound wherein the
condition associated with abnormal glutamate neurotransmission is
selected from: neuropathic pain, diabetic neuropathic pain (DNP),
cancer pain, pain related to rheumathic arthritis, inflammatory
pain, L-dopa-induced and tardive dyskinesias, Parkinson's disease,
anxiety disorders, Huntington's chorea, epilepsy, Alzheimer's
disease, positive and negative symptoms of schizophrenia, cognitive
impairment, reflux, migraine or for cognitive enhancement and/or
neuroprotection.
[0295] Further, the invention relates to a pharmaceutical
composition comprising as active ingredient at least one compound
of formula (I) as defined above or an optical isomer,
pharmaceutically acceptable salt, hydrate, solvate or polymorph
thereof, together with one or more pharmaceutically acceptable
excipients.
[0296] The invention also relates to the process for the synthesis
or preparation of a compound of formula (I) ##STR14## [0297]
wherein [0298] R.sup.1 represents chloro or bromo; [0299] R.sup.2
and R.sup.3 each independently represent hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or [0300] R.sup.2 and
R.sup.3 both together with the carbon atom of the ring represent a
carbonyl group; [0301] R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or [0302] R.sup.4 and R.sup.5 both together with
the carbon atom of the ring represent a carbonyl group; [0303]
R.sup.6 and R.sup.7 independently represent hydrogen,
C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or [0304]
R.sup.6 and R.sup.7 both together with the carbon atom of the ring
represent a carbonyl group; [0305] R.sup.2 or R.sup.3 together with
R.sup.6 and R.sup.7 may also form a bivalent radical selected from
the group CH.sub.2--CH.sub.2 and CH.sub.2--O; [0306] R.sup.8
represents a radical R.sup.9 or a radical R.sup.10, whereby one of
the two radicals R.sup.8 represents R.sup.9 and the other radical
R.sup.8 represents R.sup.10; [0307] R.sup.9 represents an aryl,
heteroaryl or heterocycle, wherein the ring system may be
optionally substituted by one or two substituents, which may be the
same or different and selected independently from halogen, amino,
hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; [0308]
R.sup.10 represents hydrogen or C.sub.1-6alkyl; and optical
isomers, pharmaceutically acceptable salts, hydrates, solvates, and
polymorphs thereof, [0309] wherein a compound of formula (II)
##STR15## [0310] is suspended in a mixture of ethanol and water and
treated with hydrochloric acid, followed by reaction with
H.sub.2NNHCOOCH.sub.3 to yield a compound of Formula (III)
##STR16## [0311] which is reacted with a compound of Formula (IV)
##STR17## [0312] to yield a compound of Formula (V) ##STR18##
[0313] which is hydrolyzed under acidic conditions to yield a
compound of Formula (VI) ##STR19## [0314] which is treated with an
amine of Formula (VII) ##STR20## [0315] in the presence of a
condensing agent, to yield a compound of Formula (I), which is
converted, if desired, to a pharmaceutically acceptable salt,
hydrate, solvate, or polymorph.
[0316] A further embodiment of the invention relates to an amine
compound of formula (VII) ##STR21## [0317] wherein [0318] R.sup.2
and R.sup.3 each independently represent hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or [0319] R.sup.2 and
R.sup.3 both together with the carbon atom of the ring represent a
carbonyl group; [0320] R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or [0321] R.sup.4 and R.sup.5 both together with
the carbon atom of the ring represent a carbonyl group; [0322]
R.sup.6 and R.sup.7 independently represent hydrogen,
C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or [0323]
R.sup.6 and R.sup.7 both together with the carbon atom of the ring
represent a carbonyl group; [0324] R.sup.2 or R.sup.3 together with
R.sup.6 and R.sup.7 may also form a bivalent radical selected from
the group CH.sub.2--CH.sub.2 and CH.sub.2--O; [0325] R.sup.8
represents a radical R.sup.9 or a radical R.sup.10, whereby one of
the two radicals R.sup.8 represents R.sup.9 and the other radical
R.sup.8 represents R.sup.10; [0326] R.sup.9 represents a cyclic
group selected from aryl, heteroaryl or heterocyclyl, wherein the
ring system may be optionally substituted by one or two
substituents, which may be the same or different and selected
independently from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; [0327] R.sup.10
represents hydrogen or C.sub.1-6alkyl.
[0328] A further embodiment of the invention relates to a process
for the synthesis of a compound of formula (I) ##STR22## [0329]
wherein [0330] R.sup.1 represents chloro or bromo; [0331] R.sup.2
and R.sup.3 each independently represent hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl or trifluoromethyl; or [0332] R.sup.2 and
R.sup.3 both together with the carbon atom of the ring represent a
carbonyl group; [0333] R.sup.4 and R.sup.5 each independently
represent hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl or
trifluoromethyl; or [0334] R.sup.4 and R.sup.5 both together with
the carbon atom of the ring represent a carbonyl group; [0335]
R.sup.6 and R.sup.7 independently represent hydrogen,
C.sub.1-6-alkyl, C.sub.3-7cycloalkyl or trifluoromethyl; or [0336]
R.sup.6 and R.sup.7 both together with the carbon atom of the ring
represent a carbonyl group; [0337] R.sup.2 or R.sup.3 together with
R.sup.6 and R.sup.7 may also form a bivalent radical selected from
the group CH.sub.2--CH.sub.2 and CH.sub.2--O; [0338] R.sup.8
represents a radical R.sup.9 or a radical R.sup.10, whereby one of
the two radicals R.sup.8 represents R.sup.9 and the other radical
R.sup.8 represents R.sup.10; [0339] R.sup.9 represents a cyclic
group selected from aryl, heteroaryl or heterocyclyl, wherein the
ring system may be optionally substituted by one or two
substituents, which may be the same or different and selected
independently from halogen, amino, hydroxyl, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl and C.sub.1-6alkoxy; [0340] R.sup.10
represents hydrogen or C.sub.1-6alkyl; [0341] and optical isomers,
pharmaceutically acceptable salts, hydrates, solvates, and
polymorphs thereof, [0342] wherein a compound of Formula (VIII)
##STR23## [0343] is dissolved in an alcoholic solvent and treated
with thionyl chloride to yield a compound of Formula IX ##STR24##
[0344] wherein PG represents C.sub.1-6alkyl, which is reduced under
standard conditions to yield a compound of Formula X ##STR25##
[0345] which is reacted with a compound of Formula (IV) ##STR26##
[0346] to yield a compound of Formula (XI) ##STR27## [0347] which
is hydrolyzed under acidic conditions to yield a compound of
Formula (VI) ##STR28## [0348] which is treated with an amine of
Formula (VII) ##STR29## [0349] in the presence of a condensing
agent, to yield a compound of Formula (I), which is converted, if
desired, to a pharmaceutically acceptable salt, hydrate, solvate,
or polymorph.
[0350] Moreover, the mGluR modulators as described above are
expected to have a high activity when administered in combination
with other substances exhibiting neurological effects via different
mechanisms.
[0351] The invention also relates to a pharmaceutical composition
comprising at least two different active ingredients, containing at
least one compound of formula (I) as defined above, and furthermore
containing at least one NMDA receptor antagonist, together with one
or more pharmaceutically acceptable excipients. These compositions
can be used for the treatment of CNS-related diseases, cognitive
enhancement and for neuro-protection.
[0352] Simultaneous administration of Group I mGluR modulators and
NMDA receptor antagonists has also been shown to provide
neuroprotection in animal models (see e.g. Zieminska et al.
Neurochemistry International, 2006, 66, 301-309; Zieminska et al.
Neurochemistry International, 2003, 43, 481-492; Zieminska et al.
Neurochemistry International, 2006, 48, 491-497).
[0353] With respect to the specific compounds as described above,
the combined therapy exhibits a greater neuroprotective effect than
monotherapy with either an mGluR modulator or an NMDA receptor
antagonist. As particularly active NMDA receptor antagonist, the
compound Memantine can be named, which is also known as
1-amino-3,5-dimethyladamantane (see U.S. Pat. No. 4,122,193; U.S.
Pat. No. 4,273,774; and U.S. Pat. No. 5,061,703).
[0354] Furthermore, the compound Neramexane, which also is known as
1-amino-1,3,3,5,5-pentamethylcyclohexane, is a further active NMDA
receptor antagonist and is disclosed in detail in U.S. Pat. No.
6,034,134 and U.S. Pat. No. 6,071,966. Memantine and Neramexane are
systemically-active noncompetitive NMDA receptor antagonists having
moderate affinity for the receptor. They exhibit strong voltage
dependent characteristics and fast blocking/unblocking kinetics
(see e.g. Gortelmeyer et al., Arzneim-Forsch/Drug Res., 1992,
42:904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999,
14:135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al.,
Curr. Pharm. Des., 2002, 8:835-43; Jirgensons et. al. Eur. J. Med.
Chem., 2000, 35: 555-565).
[0355] The combination of NMDA antagonists with mGluR5 modulators
can be realized in a single pharmaceutical composition (as
principally described in the prior art) comprising a mGluR5
modulator of the present invention and an NMDA receptor antagonist,
in one pharmaceutical formulation, or in two separate
pharmaceutical compositions or formulations, one comprising a
mGluR5 modulator of the present invention and one comprising an
NMDA receptor antagonist in a pharmaceutical formulation, to be
administered conjointly (simultaneously or sequentially).
[0356] For the sequential administration to be considered
"conjoint", however, the mGluR5 modulator of the present invention
and the NMDA receptor antagonist must be administered separated by
a time interval that still permits the resultant beneficial effect
in a mammal. For example, the mGluR5 modulator of the present
invention and the NMDA receptor antagonist must be administered on
the same day (e.g., each--once or twice daily), preferably within
an hour of each other, and most preferably simultaneously.
[0357] This invention also relates to a pharmaceutical composition
comprising a combination of a compound of formula (I) as described
above and an NMDA receptor antagonist. Of particular interest is a
composition, wherein the NMDA receptor antagonist is selected from
Memantine and Neramexane (or a combination thereof) and
pharmaceutically acceptable salts, polymorphs, hydrates and
solvates thereof.
[0358] The invention also relates to a pharmaceutical composition
comprising at least two different active ingredients, containing at
least one compound of formula (I) as defined above, and furthermore
containing at least one of L-DOPA, another dopaminomimetics (in
particular an antiparkinsonian dopaminomimetics e.g. bromocriptine,
cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and a
neuroleptic (in particular a classical neuroleptic, e.g.
haloperidol, perphenazin, chlorpromazine, metoclopramide).
[0359] These combination products can e.g. be used for the
treatment of CNS-related disorders and diseases. Because of the
antidyskinetic effect of the compounds of formula (I), drug induced
dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced
dyskinesias, dopaminomi-metic-induced dyskinesias can be treated in
addition to the conditions which are typically treated with L-Dopa,
dopaminomimetics or neuroleptics.
[0360] The invention also relates to a method of providing
neuroprotection to a living animal, including a human, comprising
the step of administering to a living animal, including a human, a
therapeutically effective amount of a composition as described.
[0361] This invention is also dealing with the compounds of formula
(I) for the use as a medicament. Furthermore, the invention relates
to the use of a compound of formula (I) for the manufacture of a
medicament for the treatment of the diseases and conditions
mentioned above.
[0362] Furthermore, the invention relates to the use of a
composition as described for the manufacture of a medicament to
provide neuroprotection in an animal, including a human.
[0363] Furthermore, the invention relates to the use of a compound
of formula (I) in the manufacture of a medicament for treatment of
a condition associated with abnormal glutamate neurotransmission or
in which modulation of mGluR5 receptors results in therapeutic
benefit. The disorders which can be treated have already been
described above. Such conditions and indications include:
[0364] a) For mGluR5 modulators: chronic pain, neuropathic pain,
diabetic neuropathic pain (DNP), cancer pain, pain related to
rheumathic arthritis, inflammatory pain, L-dopa-induced
dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced
dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced
dyskinesias in Parkinson's disease therapy, tardive dyskinesias,
Parkinson's disease, anxiety disorders, panic disorders, anxiety
and panic disorders, social anxiety disorder (SAD), generalized
anxiety disorder, substance-induced anxiety disorder, eating
disorders, obesity, binge eating disorders, Huntington's chorea,
epilepsy, Alzheimer's disease, positive and negative symptoms of
schizophrenia, cognitive impairment, functional gastrointestinal
disorders, gastroesophageal reflux disease (GERD), migraine,
irritable bowel syndrome (IBS), or for cognitive enhancement and/or
neuroprotection.
[0365] b) For negative modulation of mGluR5: chronic pain,
neuropathic pain, diabetic neuropathic pain (DNP), cancer pain,
pain related to rheumathic arthritis, inflammatory pain,
L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias,
L-dopa-induced dyskinesias in Parkinson's disease therapy,
dopaminomimetic-induced dyskinesias in Parkinson's disease therapy,
tardive dyskinesias, Parkinson's disease, anxiety disorders, panic
disorders, anxiety and panic disorders, social anxiety disorder
(SAD), generalized anxiety disorder, substance-induced anxiety
disorder, eating disorders, obesity, binge eating disorders,
migraine, irritable bowel syndrome (IBS), functional
gastrointestinal disorders, gastroesophageal reflux disease (GERD),
Huntington's chorea and/or epilepsy.
[0366] c) For positive modulation of mGluR5: Alzheimer's disease,
positive and/or negative symptoms of schizophrenia, cognitive
impairment, or for cognitive enhancement and/or
neuroprotection.
[0367] The mGluR5 negative modulators in general and in particular
the compounds of formula (I) according to the invention can be used
for the treatment of binge eating disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0368] For the purpose of the present invention, in the compounds
of formula (I) the carbon atom content of various
hydrocarbon-containing moieties is indicated by a prefix
designating the minimum and maximum number of carbon atoms in the
moiety, i.e., the prefix C.sub.i-j indicates a moiety of the
integer "i" to the integer "j" carbon atoms, inclusive.
[0369] Thus, for example, (C.sub.1-3)alkyl refers to alkyl of one
to three carbon atoms (i.e. 1, 2 or 3 carbon atoms), inclusive,
(methyl, ethyl, propyl, and isopropyl), straight and branched forms
thereof, (C.sub.1-6) for instance refers to a radical of one to six
carbon atoms (i.e. 1, 2, 3, 4, 5 or 6 carbon atoms).
[0370] As used herein, the following definitions are applicable
unless otherwise described, the term "C.sub.1-6alkyl" represents
straight or branched chain alkyl groups which may be optionally
substituted by one or more substituents selected from halogen,
trifluoromethyl, C.sub.1-6alkoxy, amino, hydroxy,
C.sub.1-6alkylamino, and di-(C.sub.1-6alkyl)amino. Examples of such
alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl,
tert-butyl, --CF.sub.3, --C.sub.2F.sub.5, --CBr.sub.3 and
--CCl.sub.3.
[0371] The term "C.sub.2-6alkenyl" represents straight or branched
chain alkenyl groups. The term "C.sub.1-6alkoxy" represents
straight or branched chain --O--C.sub.1-6alkyl groups which may be
optionally substituted by one or more substituents selected from
halogen, trifluoromethyl, amino, hydroxy, C.sub.1-6alkylamino and
di-(C.sub.1-6alkyl)amino. Examples of such alkoxy groups include
methoxy, ethoxy, n-propoxy, i-propoxy, --OCF.sub.3 and
--OC.sub.2F.sub.5.
[0372] The term "cycloC.sub.3-12alkyl" represents monocyclic or
bicyclic, or tricyclic alkyl groups, including cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and
adamantanyl, which may be optionally substituted by one or more
substituents, which may be the same or different, selected
independently from halogen, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, amino, hydroxy,
nitro, cyano, cyanomethyl, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkylamino, and di-(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino, and C.sub.1-6alkylenedioxy.
[0373] The term "aryl" represents phenyl or naphthyl, wherein the
phenyl or naphthyl group is optionally substituted by one or more
substituents, which may be the same or different, selected
independently from halogen, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl C.sub.2-6alkenyl,
C.sub.1-6alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylamino, di-(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl,
morpholinyl, and piperazinyl, cycloC.sub.3-12alkyl or optionally
C.sub.1-6alkylenedioxy.
[0374] The term "acyl" includes --(C.dbd.O)-alkyl; --(C.dbd.O)aryl;
--(C.dbd.O)-aralkyl, --(C.dbd.O)-heterocyclyl,
C.sub.1-6-alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl,
C.sub.2-6alkenylcarbonyl, C.sub.2-6alkynylcarbonyl, arylcarbonyl,
heteroarylcarbonyl or heterocyclylcarbonyl, wherein the terms
alkyl, aryl and heterocyclyl are defied as above. Examples are
acetyl, propionyl, benzoyl or pivaloyl.
[0375] The term "heteroaryl" represents an aromatic 5-6 membered
ring containing from one to four heteroatoms selected from oxygen,
sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered
ring containing from one to four heteroatoms selected from oxygen,
sulfur and nitrogen fused with a benzene ring or a 5-6 membered
ring containing from one to four heteroatoms selected from oxygen,
sulfur and nitrogen, wherein the heteroaryl group may be optionally
substituted by one or more substituents, which may be the same or
different, selected independently from halogen, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.1-6alkoxy, amino, hydroxy, nitro, cyano,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkoxycarbonyloxy,
C.sub.1-6alkylamino, and di-(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino, aminocarbonyl,
N--C.sub.1-6alkylaminocarbonyl,
di-N,N--C.sub.1-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl,
morpholinyl, cycloC.sub.3-12alkyl, C.sub.1-6alkylenedioxy and aryl.
Representative heteroaryl groups include furanyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,
triazinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl,
indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl,
quinoxalinyl, cinnolinyl, naphtyridinyl, and isoquinolinyl.
Examples are pyridyl, pyrimidyl, thienyl, furyl and others.
[0376] The term "heterocyclyl" represents a saturated or
unsaturated non-aromatic 3 to 12 membered ring comprising one to
four heteroatoms selected from oxygen, sulfur and nitrogen, and a
saturated or unsaturated non-aromatic bicyclic ring system having 3
to 12 members comprising one to six heteroatoms selected from
oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring
system is optionally substituted by one or more substituents
selected independently from a halogen, trifluoromethyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, amino, hydroxy,
nitro, cyano, C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylamino,
di-C.sub.1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl,
pyridinyl, and aryl; examples of such heterocyclyl groups include
piperidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl,
pyrazolidinyl, pyrrolidinyl, or piperazinyl, wherein the
heterocyclic ring or ring system is linked to the group to which it
is attached optionally via nitrogen or a carbon atom.
[0377] The term "halogen" represents fluorine, chlorine, bromine
and iodine.
[0378] The compounds of the present invention are usually named
according to the IUPAC or CAS nomenclature system. Abbreviations
which are well known to one of ordinary skill in the art may be
used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h"
for hour or hours, and "rt" for room temperature).
[0379] The term "analog" or "derivative" is used herein in the
conventional pharmaceutical sense, to refer to a molecule that
structurally resembles a reference molecule, but has been modified
in a targeted and controlled manner to replace one or more specific
substituents of the referent molecule with an alternate
substituent, thereby generating a molecule which is structurally
similar to the reference molecule. Synthesis and screening of
analogs (e.g., using structural and/or biochemical analysis), to
identify slightly modified versions of a known compound which may
have improved or biased traits (such as higher potency and/or
selectivity at a specific targeted receptor type, greater ability
to penetrate blood-brain barriers, fewer side effects, etc.) is a
drug design approach that is well known in pharmaceutical
chemistry.
[0380] In addition, using methods known to those skilled in the
art, analogs and derivatives of the compounds of the invention can
be created which have improved therapeutic efficacy, i.e., higher
potency and/or selectivity at a specific targeted receptor type,
either greater or lower ability to penetrate mammalian blood-brain
barriers (e.g., either higher or lower blood-brain barrier
permeation rate), fewer side effects, etc.
[0381] The phrase "pharmaceutically acceptable", as used in
connection with compositions of the invention, refers to molecular
entities and other ingredients of such compositions that are
physiologically tolerable and do not typically produce untoward
reactions when administered to a mammal (e.g., human). Preferably,
as used herein, the term "pharmaceutically acceptable" means
approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopeia or other generally
recognized pharmacopeia for use in mammals, and more particularly
in humans.
[0382] Compounds of the present invention may be in the form of
pharmaceutically acceptable salts. "Pharmaceutically acceptable
salts" refers to those salts which possess the biological
effectiveness and properties of the parent compound and which are
not biologically or otherwise undesirable. The nature of the salt
is not critical, provided that it is non-toxic and does not
substantially interfere with the desired pharmacological
activity.
[0383] It will be appreciated by those skilled in the art that
compounds of the invention having a chiral center may exist in and
be isolated in optically active and racemic forms. Some compounds
may exhibit polymorphism. It is to be understood that the present
invention encompasses any racemic, optically active, polymorphic,
tautomeric, or stereoisomeric form, or mixture thereof, of a
compound of the invention, which possesses the useful properties
described herein.
[0384] All patents, applications, publications, test methods,
literature, and other materials cited in this application are
hereby incorporated by reference.
[0385] The following Schemes 1-3 describe the preparation of
compounds of Formula (I) of the present invention. All of the
starting materials may be prepared by procedures described in these
schemes, by procedures well known to one of ordinary skill in
organic chemistry, or may be obtained commercially. All of the
final compounds of the present invention may be prepared by
procedures described in these charts or by procedures analogous
thereto, which would be well known to one of ordinary skill in
organic chemistry. All of the variables used in the schemes are as
defined below or as in the claims.
[0386] The compounds containing one or more chiral centers can be
prepared as racemates or mixtures of various stereoisomers and then
separated. However, they also can be prepared by a special
enantioselective synthesis.
[0387] For several of the chiral compounds, the enantiomers differ
in pharmacological activity.
[0388] Compounds of the present invention may be synthesized
according to Scheme 1.
[0389] 5-Nitro-1H-pyrazole-3-carboxylic acid 1 is reduced under
standard conditions, such as treatment with hydrogen in the
presence of palladium(0) on carbon in a solvent such as methanol,
to yield 5-amino-1H-pyrazole-3-carboxylic acid 2. Compound 2 is
reacted with di-aldehyde 3, carrying a bromo or chloro substituent
at the R.sup.1 position, under acid conditions, such as acetic
acid, at elevated temperatures to give 6-bromo- or
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4). A
compound of Formula I is prepared from 4 via reaction with an
appropriate secondary amine 5 in the presence of a condensation
agent, including, for example,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate ("TBTU") or
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). ##STR30##
[0390] The amines (5) are commercially available or may be prepared
according to literature procedures (see, for example, Bull. Soc.
Chim. Belg., v. 71, 1962; p. 592; US 2002/049223 A1 (2002/04/25);
Chem. Ber., 84, 1951, p. 795-798; Bull. Soc. Chim. Fr. 5, 4, 1937,
p. 1265-1269; Zh. Obshch. Khim., 7, 1937, p. 1999-2004; Chem.
Pharm. Bull., EN, 31, 8, 1983, p. 2583-2592; Tetrahedron, 28, 1972,
p. 5999-6004; J. Org. Chem., 34, 8, 1969, p. 2478; Pharm. Chem. J.
(Engl. Tran.); 5; 5; 1971, p. 260; Khfzan; Khim. Famm. Zh., 5, 5,
1971, p. 13).
[0391] Compound 4 may also be prepared according to Scheme 2.
##STR31## ##STR32##
[0392] 5-Nitro-3-pyrazole carboxylic acid 1 is dissolved in an
alcoholic solvent, e.g. methanol or ethanol, and reacted with
thionyl chloride to give compound 1a bearing an alkyl ester group.
The term "PG" denotes any C.sub.1-6 alkyl chain, including branched
alkyl chains, for example, methyl and ethyl groups.
5-Nitro-3-pyrazole-carboxylic acid alkyl ester 1a is reduced under
standard conditions, such as treatment with hydrogen in the
presence of palladium(0) on carbon in a solvent such as methanol,
to yield 5-amino-1H-pyrazole-3-carboxylic acid alkyl ester 2a.
Compound 2a is reacted with di-aldehyde 3, carrying a bromo or
chloro substituent at the R.sup.1 position, under acid conditions,
such as acetic acid, at elevated temperatures to give 6-bromo- or
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid alkyl ester
(4a). The ester 4a is hydrolyzed under acidic conditions such as
sulphuric acid (30%) to yield 6-bromo- or
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4. A compound
of Formula I is prepared from 4 via reaction with an appropriate
secondary amine 5 as shown in Scheme 1.
[0393] Compound 4 may also be prepared according to Scheme 3.
[0394] Ethyl 3-cyano-2-oxopropionate sodium salt ("NaCOPE") 6 is
treated with methyl hydrazino formiate to yield ethyl
5-aminopyrazole-3-carboxylate 7. Compound 7 is reacted with
dialdehyde 3, carrying a bromo or chloro substituent at the R.sup.1
position, under acidic conditions, to yield ethyl 6-bromo- or
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylate 8. The ester 8 is
hydrolyzed under acidic conditions to yield 6-bromo- or
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4. A compound
of Formula I is prepared from 4 via reaction with an appropriate
secondary amine 5 as shown in Scheme 1. ##STR33##
[0395] It will be appreciated that in the above transformations it
may be necessary or desirable to protect any sensitive groups in
the molecule of the compound in question in order to avoid
undesirable side reactions.
EXPERIMENTAL PART
[0396] Hereinafter, "DMF" is defined as N,N-dimlethylformamide,
"HCl" as hydrochloric acid, "DMSO" as dimethylsulfoxide and "TBTU"
as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate.
Preparation 1
5-Nitro-3-pyrazole-carboxylic acid methyl ester
[0397] 5-Nitro-3-pyrazol carboxylic acid (21.44 g, 136.5 mmol) is
dissolved in dry methanol (200 mL). Then, thionyl chloride (9.9 mL,
136.5 mmol) is added slowly in a drop wise manner at RT. The
reaction mixture is heated over night under reflux and under argon
atmosphere. After cooling down, the solvent is evaporated under
vacuum and the crude material is heated with boiling hexane (200
ml). After cooling down and removal of the hexane, the material is
washed two times with 200 ml pentane. Then, the solvent is removed
and the product is dried under vacuum to give
5-nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g,
95.7%).
Preparation 2
5-Amino-3-pyrazole-carboxylic acid methyl ester
[0398] 5-Nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g,
130.61 mmol) is dissolved in each 160 mL THF und glacial acetic
acid. Then, Pd--C (10%, 4.36 g) are added and the reaction is
stirred for 6 days under hydrogen atmosphere at RT. Then, the
mixture is filtered over celite and the solvent is removed under
vacuum. The crude material is dissolved in methylene chloride (800
mL) and sodium hydrogen carbonate (200 g) are added, filtered and
the solvent is again removed under vacuum. This procedure is
repeated until the acetic acid smell is lost.
5-Amino-3-pyrazole-carboxylic acid methyl ester is isolated in high
yields (16.91 g, 91.7%).
Preparation 3
6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl
ester
[0399] 5-Amino-3-pyrazolcarboxylic acid methyl ester (16.91 g,
119.8 mmol) is dissolved in ethanol (2.4 L) and hydrochloric acid
(37%, 12.5 mL, 150 mmol) is added. Then, a solution of
2-bromo-malonealdehyde (18.9 g, 125.2 mmol) is dissolved in ethanol
(1.4 L) and is quickly added in a drop wise manner at RT. After 30
min, a precipitation is observed; after 6 hours the precipitate is
removed and washed with 50 ml ethanol and thereafter with 50 ml
diethyl ether. Here, 4.19 g of the clean product are isolated.
After evaporation of the filtrate and crystallisation, additional
1.43 g product are obtained to yield
6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester
(5.62 g, 18.3% d. Th.). In case of a smaller scale reaction with
only 1 g of the starting amine 5-amino-3-pyrazolcarboxylic acid
methyl ester, the yield is much better e.g. 68%.
Preparation 4
6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid
[0400] 6-Bromopyrazolo[1,5a]pyrimidin-2-carboxylic acid methyl
ester (3.76 g, 14.68 mmol) is heated in 600 mL water, 190 mL
sulphuric acid (30%) and 50 mL of the methanol/water mixture is
removed from the reaction mixture via distillation. After cooling
down, 50 mL water is added, the mixture is heated again and 50 mL
of the alcohol-water mixture is removed. This cycle is repeated 6
times, the reaction mixture is cooled to RT and filtered over a
glass filter. The crude material is washed with water (100 mL),
acetone (20 mL) and ether (20 mL) and dried under vacuum to give
6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid (2.61 g, 10.78
mmol; 73.5%).
[0401] Physical characteristics are as follows: .sup.1H NMR (DMSO):
(ppm) 13.4, 9.7, 8.7, 7.2.
6-Chloro-pyrazolo[1,5a]pyrimidine-2-carboxylic acid
[0402] The hydrolysis of methyl
6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate is performed under
similar conditions as described above for methyl
6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate.
Preparation 5
Ethyl 5-aminopyrazole-3-carboxylate
[0403] A 10 L three-necked flask is equipped with mechanical
stirrer, reflux condenser and nitrogen inlet. To ethyl
3-cyano-2-oxopropionate sodium salt ("NaCOPE") (653.18 g; 4.0 mol),
585 mL of water, 3.6 L of ethanol and 350 mL of hydrochloric acid
(12N; 4.2 mol) are added. The resulting suspension is stirred at RT
for 15 min. Then, methyl hydrazino formiate (356.0 g; 3.95 mol) is
added as a solid material. A slightly exothermic reaction occurs.
After the mixture is stirred at RT for 6 h, another portion of
methyl hydrazino formiate (12.0 g; 133.7 mmol) is added and the
orange suspension is stirred at RT over night. Then potassium
carbonate (K.sub.2CO.sub.3, 300.0 g; 2.17 mol) is added, followed
by 250 mL of water. The internal temperature rises to 60.degree. C.
and a vigorous evolution of gas starts. The mixture is heated at
reflux for four hours. After cooling to RT, the alcohol is
evaporated to yield a red paste, which is taken up in 1 L of water
and 3 L of ethyl acetate. The aqueous phase is extracted with
another 500 mL portion of ethyl acetate. The organic extracts are
washed with brine and dried over sodium sulfate (Na.sub.2SO.sub.4).
After filtration the solvent is evaporated to yield 330 g of a
brown paste. This crude product is mixed with 1 L of ether to give
a light brown solid, which is separated from an orange liquid phase
by filtration. The solid is dried under vacuum to yield 229.12 g
(7). The liquid phase is evaporated; the residue is taken up in 250
mL of ether and cooled to -30.degree. C. to yield another 15.09 g
of 7. The total yield of 7 is 244.21 g (1.57 mol; 39.3%). Physical
characteristics are as follows:
[0404] .sup.1H-NMR (DMSO): .delta. (ppm) 1.26, 4.21, 5.0, 5.76,
12.12.
Preparation 6
Ethyl 6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate
[0405] A 2 L round bottom flask is charged with ethyl
5-aminopyrazole-3-carboxylate (7) (44.92 g; 289.50 mmol), 1.2 L of
ethanol and 27 mL of hydrochloric acid (12N; 324.0 mmol).
2-Bromomalonaldehyde (43.71 g; 289.54 mmol) is added as a solid to
the resulting yellow solution. A light brown solution is formed,
from which a tan solid started to precipitate after 15 min. The
suspension is stirred at RT over night and thereafter, filtered
with suction. The solid is washed with 200 mL of ether to yield
62.50 g of (8a) after drying at 40.degree. C./1 Torr. Additional
crystals are isolated from the filtrate by concentration and
cooling to -30.degree. C. A total yield of 74.12 g (274.4 mmol;
94.8%) of 8a is obtained with a HPLC-purity>97%.
[0406] Physical characteristics are: .sup.1H-NMR (DMSO): .delta.
(ppm) 1.35, 4.39, 7.24, 8.74, 9.68.
Preparation 7
Sodium Salt of Chloromalonaldehyde
[0407] A 2 L Schlenk flask equipped with a 500 mL addition funnel
is charged with mucochloric acid (100.0 g; 592.0 mmol) dissolved in
400 mL of ethanol. Then, a solution of aniline (108 mL; 1.18 mmol)
in 400 mL of ethanol is added over a period of 5 min. The reaction
proceeds exothermic via the formation of large amounts of carbon
dioxide. Thereafter, the orange solution is heated to reflux for 5
min and then cooled down to RT. Overnight, a yellow precipitate is
formed. 500 mL of HCl (1N) are added and the suspension is filtered
with suction. The residue is washed with 200 mL of ethanol and 500
mL of ether. It is dried at 40.degree. C./1 Torr to yield the
hydrochloride of the dianilide (A) (107.8 g; 313.8 mmol; 53.7%) as
a yellow solid which is used for the next step without further
purification. In a 10 L three necked flask, 5 L of water are heated
to reflux and the crude dianilide (A) (81.2 g; 239.3 mmol) is added
in 6 portions over 15 min. The foaming suspension is heated for a
further 15 min. Then, the mixture is cooled to RT overnight. After
filtration with suction, the residue is suspended in 150 mL of
ethanol and treated in an ultrasonic bath for 2 min. The mixture is
filtered again with suction and washed with 200 mL of ether. The
pale yellow residue is dried at 40.degree. C./1 Torr to yield 39.68
g of the monoanilide of chloromalonaldehyde (B) (218.5 mmol; 91.2%)
with a HPLC-purity>97%. A 1 L round bottom flask is charged with
39.68 g (B) (218.5 mmol) and 200 mL of NaOH (2N solution). It is
heated to reflux for about 5 min until the solid is dissolved. At
an internal temperature of 45.degree. C., ethyl acetate (40 mL) is
added. The alkaline aqueous layer is washed with a 40 mL portion of
ethyl acetate and cooled to 5.degree. C. After 12 hrs, the
colorless needles are filtered off and washed with 50 mL of ethanol
and 200 mL of ether. Concentration and cooling of the mother liquor
yielded another crop of crystals. In total, 29.16 g (159.7 mmol;
73.1%) of the trihydrate of the sodium salt of chloromalonaldehyde
(C) are isolated after drying at 40.degree. C./1 Torr.
Preparation 8
Ethyl 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate
[0408] A 100 mL round bottom flask is charged with ethyl
5-aminopyrazole-3-carboxylate (7) (2.0 g; 12.89 mmol) and 50 mL of
ethanol. To this solution hydrogen chloride (12 N; 1.2 mL; 14.4
mmol) is added. Then, the sodium salt of chloromalonaldehyde (C)
(2.35 g; 12.89 mmol) is added as a solid in one portion. The
resulting suspension is stirred at RT over night. Thereafter, it is
filtered with suction and washed with 50 mL of ether. The residue
is extracted with 120 mL of chloroform in a soxleth apparatus for 5
h. Then, the solvent is evaporated from the organic extract
yielding 2.44 g of 8b (10.8 mmol; 83.9%) with >97% by HPLC.
[0409] Physical characteristics are: .sup.1H-NMR (DMSO): (ppm)
1.35, 4.39, 7.25, 8.72, 9.63.
Preparation 9
6-Halogeno-pyrazolo[1,5a]pyrimidine-2-carboxylic acids
[0410] The hydrolysis of the ethyl
6-halogeno-pyrazolo[1,5a]pyrimidine-2-carboxylates (8) with aqueous
acids leads to the carboxylic acids (4) in good yields (>80%).
Hydrochloric acid is used to hydrolyze the 6-chloro-ester. The
6-bromo-derivative is hydrolyzed using sulfuric acid. In a typical
hydrolysis the compounds (8) are suspended in water and the acid is
added. Then, small amounts of alcohol-water-azeotrope are distilled
off until no more ester is detected by TLC (MeCN+H2O=10+2, plate
type: Alugram SIL G/UV254). The suspensions are cooled by means of
an ice-water bath and filtered with suction. The residues are
washed with water, acetone and ether. After drying at 40.degree.
C./1 Torr the 6-halogenopyrazolo[1,5a]pyrimidine-2-carboxylic acids
(6) are examined by HPLC.
6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid
[0411] A 500 mL round bottom flask is charged with ethyl
6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate (2.0 g; 7.41 mmol)
and 240 mL of water. After addition of diluted sulfuric acid (30
vol %; 62 mL) the suspension is heated to reflux and 20 mL of an
ethanol-waterazeotrope is distilled off. 20 mL of water are added
to the suspension and another 20 mL portion is distilled off. After
eight of these cycles, no more ester is detected by TLC. The
mixture is cooled to 10.degree. C. by means of an ice-bath. It is
filtered with suction and washed with 100 mL of water, followed by
20 mL of acetone and 100 mL of ether. The residue is dried at
40.degree. C./1 Torr to yield 1.54 g (6a) (6.36 mmol; 83.5) as a
beige powder.
[0412] Physical characteristics are as follows: .sup.1H-NMR (DMSO):
(ppm) 7.21, 8.75, 9.70, 13.44.
6-Chloro-pyrazolo[1,5a]pyrimidine-2-carboxylic acid
[0413] The hydrolysis of ethyl
6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate is performed under
similar conditions as described above for ethyl
6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate.
Building Block Syntheses:
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester
[0414] ##STR34##
[0415] A solution of N-Boc-4-piperidone (2 mmol) in THF (4 mL) is
cooled to -78.degree. C. and a solution of LiHMDS (2.6 mmol) is
added over 15 min. The reaction mixture is stirred for 20 min.
Tf.sub.2NPh (2.4 mmol) solution in THF (3 mL) is added at
-78.degree. C. and resulting mixture is stirred for 5 min. Reaction
vessel is then placed in an ice-bath and the mixture is stirred for
additional 2 his. Solvent is evaporated in vacuo and the solid
residue is partitioned between water and methylene chloride.
Organic phase is dried over anhydrous Na.sub.2SO.sub.4. Product
obtained after evaporation of organic phase is sufficiently pure
for further transformation.
[0416] LC/MS: m/z=200 (MH.sup.+)
[0417] .sup.1H NMR (CDCl.sub.3) .delta.: 1.45, 2.42, 3.61, 4.02,
5.74.
3',6'-Dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl
ester
[0418] ##STR35##
[0419] A solution of 1.68 mmol of 3-pyridyl boronic acid, 0.105
mmol of Pd[PPh.sub.3].sub.4, and 0.84 mmol of
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester in 3 mL of THF is combined with 1.68 mmol of
Na.sub.2CO.sub.3, 2.52 mmol LiCl and 1 mL of water. The
heterogenuous mixture is heated by microwaves at 120.degree. C. for
30 min, and then partitioned between aqueous sodium carbonate
solution and methylene chloride. The organic phase is separated,
dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo. The
residue is purified by flash column chromatography to provide the
title compound.
[0420] LC/MS: m/z=261 (MH.sup.+)
1',2',3',6'-Tetrahydro-[3,4']bipyridinyl
[0421] ##STR36##
[0422] 3',6'-Dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid
tert-butyl ester (0.2 mmol) is dissolved in a 20% mixture (1 mL) of
trifluoroacetic acid in dry methylene chloride. The reaction
solution is stirred for 1 h at room temperature, and then
evaporated in vacuo. The resulting amine salt is sufficiently pure
for the next transformation.
[0423] LC/MS: m/z=161 (MH.sup.+)
2-Methyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid phenyl
ester
[0424] ##STR37##
[0425] A solution of 4-methoxypyridine (3.57 mmol) in THF (5 mL) is
cooled to -30.degree. C. MeMgCl solution (3.93 mmol) is then added
followed by dropwise addition of ClCO.sub.2Ph (3.93 mmol). The
resulting reaction mixture is stirred for 30 min at -30.degree. C.,
and acidified with 10% HCl solution. The mixture is allowed to warm
up to room temperature and is extracted with ethyl acetate.
Combined organic phase is successively washed with saturated
bicarbonate and brine solution, and dried over anhydrous
Na.sub.2SO.sub.4. The crude product obtained after evaporation of
the solvent is purified by flash column chromatography. Resulting
colorless oily product solidifies upon standing.
[0426] LC/MS: m/z=232 (MH.sup.+)
[0427] .sup.1H NMR (CDCl.sub.3) .delta.: 1.38, 2.40, 2.97, 4.87,
5.44, 7.15-7.46, 7.87.
2-Methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxyli-
c acid phenyl ester
[0428] ##STR38##
[0429] L-Selectride (0.26 mmol) solution is added dropwise to
2-Methyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid phenyl
ester (0.22 mmol) in THF (2 mL) at -78.degree. C. The resulting
solution is stirred for 2 hrs. Tf.sub.2NPh (0.29 mmol) is added at
-35.degree. C. and the solution is stirred for another 2 hrs.
Solvent is evaporated in vacuo and the solid residue is partitioned
between water and methylene chloride. Organic phase is dried over
anhydrous Na.sub.2SO.sub.4. The crude product obtained after
evaporation of the solvent is purified by flash column
chromatography. Resulting product appears as a single isomer as
evidenced by gas chromatography.
[0430] LC/MS: m/z=366 (MH.sup.+)
[0431] .sup.1H NMR (CDCl.sub.3) .delta.: 1.31, 2.17, 2.94, 3.88,
4.65, 4.87, 6.96-7.48.
6-Methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxyli-
c acid phenyl ester
[0432] ##STR39##
[0433] L-Selectride (0.21 mmol) solution is added dropwise to
2-Methyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid phenyl
ester (0.22 mmol), in THF (2 mL) at -78.degree. C. The resulting
solution is stirred for 2 hrs. Tf.sub.2NPh (0.29 mmol) is added at
0.degree. C. and the solution is stirred for another 2 hrs. Solvent
is evaporated in vacuo and the solid residue is partitioned between
water and methylene chloride. Organic phase is dried over anhydrous
Na.sub.2SO.sub.4. The crude product obtained after evaporation of
the solvent is purified by flash column chromatography. Resulting
product is a mixture of isomeric triflates in a ratio 4:1 as
evidenced by gas chromatography.
[0434] LC/MS: m/z=366 (MH.sup.+)
[0435] .sup.1H NMR (CDCl.sub.3) .delta.: 1.32, 2.32, 2.61-2.83,
3.07-3.36, 4.40, 4.81-4.95, 5.79, 7.09-7.42.
2-Methyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid phenyl
ester
[0436] ##STR40##
[0437] A solution of 0.55 mmol of phenyl boronic acid, 0.035 mmol
of Pd[PPh.sub.3].sub.4, and 0.27 mmol of
2-methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxyl-
ic acid phenyl ester in 5 mL of THF is combined with 0.55 mmol of
K.sub.2CO.sub.3, and 1 mL of water. The heterogeneous mixture is
heated by microwaves at 120.degree. C. for 30 min, and then
partitioned between aqueous sodium carbonate solution and methylene
chloride. The organic phase is separated, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated in vacuo. The residue is purified
by flash column chromatography to provide the title compound.
[0438] LC/MS: m/z=294 (MH.sup.+)
[0439] .sup.1H NMR (CDCl.sub.3) .delta.: 1.24, 2.31, 2.87, 3.88,
4.52, 4.78, 6.01, 7.02-7.41.
2-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine
[0440] ##STR41##
[0441] 2-Methyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid
phenyl ester is dissolved in a mixture of 2 mL of isopropyl alcohol
and 2 mL of 2 M aqueous LiOH solution. The resulting reaction
mixture is refluxed for 48 hrs. The solution is concentrated in
vacuo and extracted with diethyl ether. Combined organic phase is
washed with brine and dried over NaOH pellets. Solvent is
evaporated and resulting product is used without further
purification.
[0442] LC/MS: m/z=174 (MH.sup.+) Final Coupling Reaction General
Scheme: ##STR42##
[0443] Acid A (1 equiv., 0.4 mmol) is mixed with TBTU (1.1 equiv.,
0.145 g, 0.45 mmol) in dry CH.sub.3CN. Then, Et.sub.3N (2.5 equiv.,
0.14 mL, 1 mmol) is added. The corresponding amine (1 equiv., 0.4
mmol) is added. The reaction is stirred at 50.degree. C. for 2 h to
adjust full resolution of the acid. Then, the reaction is carried
out at room temperature. The reaction is monitored with TLC. When
the reaction is over, some water is added to the reaction mixture.
If a precipitate formed it is filtered off, washed with 5% ammonia
solution and ether. If an oil formed it is extracted with methylene
chloride and separated on a column (different systems) providing
the final compounds in good to moderate yields.
[0444] The following compounds according to the invention are
prepared as examples, which are intended as an illustration of and
not a limitation upon the scope of the invention:
Example 1
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-
-yl)-methanone
[0445] ##STR43##
[0446] To a solution of
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.7 g, 2.9
mmol, 1.0 equiv) and TBTU (1.0 g, 3.1 mmol, 1.1 equiv) in dry
CH.sub.3CN (20 mL), triethylamine (1 mL, 7.25 mmol, 2.5 equiv) and
4-phenyl-1,2,3,6-tetrahydro-pyridine (0.56 g, 2.9 mmol, 1 equiv)
are added. The reaction mixture is stirred at 50.degree. C. for 2 h
and then at room temperature for 8 h. The reaction mixture is
diluted with water (10 mL). The precipitate is filtered off, washed
sequentially with 50% aqueous ethanol, water, 5% aqueous ammonia,
and diethyl ether and dried to provide 0.539 g of the title
compound.
[0447] Yield: 48%
[0448] LC/MS: m/z=383 (MH.sup.+)
[0449] .sup.1H NMR (d.sub.6-DMSO) .delta.: 2.58, 3.89, 4.31 4.42,
6.09 6.23, 7.02, 7.25, 7.34, 7.43, 8.68, 9.58.
Example 2
6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-
-yl)-methanone
[0450] ##STR44##
[0451] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0452] LC/MS: m/z=339 (MH.sup.+)
Example 3
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[2,4']bipyridi-
nyl-1'-yl)-methanone
[0453] ##STR45##
[0454] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1',2',3',6'-tetrahydro-[2,4']bipyridinyl to provide the title
compound in moderate yield.
[0455] LC/MS: m/z=340 (MH.sup.+)
Example 4
6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-phenyl-3,6-dihydro-2H-pyridin-1--
yl)-methanone
[0456] ##STR46##
[0457] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 5-Phenyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0458] LC/MS: m/z=384 (MH.sup.+)
Example 5
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[2,4']bipyridin-
yl-1'-yl)-methanone
[0459] ##STR47##
[0460] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
1',2',3',6'-tetrahydro-[2,4']bipyridinyl to provide the title
compound in moderate yield.
[0461] LC/MS: m/z=385 (MH.sup.+)
Example 6
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[3,4']bipyridi-
nyl-1'-yl)-methanone
[0462] ##STR48##
[0463] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1',2',3',6'-tetrahydro-[3,4']bipyridinyl to provide the title
compound in moderate yield.
[0464] LC/MS: m/z=340 (MH.sup.+)
Example 7
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3',6'-dihydro-2'H-[3,4']bipyridin-
yl-1'-yl)-methanone
[0465] ##STR49##
[0466] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
1',2',3',6'-tetrahydro-[3,4']bipyridinyl to provide the title
compound in moderate yield.
[0467] LC/MS: m/z=385 (MH.sup.+)
[0468] .sup.1H NMR (CDCl.sub.3) .delta.: 8.83-8.50, 7.92-7.66,
7.46-7.10, 6.10, 4.53, 4.08, 2.66.
Example 8
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4']bipyridinyl-
-1-yl)-methanone
[0469] ##STR50##
[0470] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1,2,3,6-tetrahydro-[4,4']bipyridinyl to provide the title
compound in moderate yield.
[0471] LC/MS: m/z=340 (MH.sup.+)
Example 9
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4']bipyridinyl--
1-yl)-methanone
[0472] ##STR51##
[0473] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
1,2,3,6-tetrahydro-[4,4']bipyridinyl to provide the title compound
in moderate yield.
[0474] LC/MS: m/z=385 (MH.sup.+)
Example 10
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl--
1-yl)-methanone
[0475] ##STR52##
[0476] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
1,2,5,6-tetrahydro-[3,4']bipyridinyl to provide the title compound
in moderate yield.
[0477] LC/MS: m/z=385 (MH.sup.+)
Example 11
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl-
-1-yl)-methanone
[0478] ##STR53##
[0479] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1,2,5,6-tetrahydro-[3,4']bipyridinyl to provide the title
compound in moderate yield.
[0480] LC/MS: m/z=340 (MH.sup.+)
Example 12
[0481]
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipy-
ridinyl-1-yl)-methanone ##STR54##
[0482] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1,2,5,6-tetrahydro-[3,3']bipyridinyl to provide the title
compound in moderate yield.
[0483] LC/MS: m/z=385 (MH.sup.+)
Example 13
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4']bipyridinyl-
-1-yl)-methanone
[0484] ##STR55##
[0485] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1,2,5,6-tetrahydro-[3,3']bipyridinyl to provide the title
compound in moderate yield.
[0486] LC/MS: m/z=340 (MH.sup.+)
Example 14
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5',6'-dihydro-2'H-[2,3']bipyridin-
yl-1'-yl)-methanone
[0487] ##STR56##
[0488] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
1',2',5',6'-tetrahydro-[2,3']bipyridinyl to provide the title
compound in moderate yield.
[0489] LC/MS: m/z=385 (MH.sup.+)
Example 15
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5',6'-dihydro-2'H-[2,3']bipyridi-
nyl-1'-yl)-methanone
[0490] ##STR57##
[0491] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 1',2',5',6'-tetrahydro-[2,3']bipyridinyl to provide the title
compound in moderate yield.
[0492] LC/MS: m/z=340 (MH.sup.+)
Example 16
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-thiophen-2-yl-3,6-dihydro-2H-p-
yridin-1-yl)-methanone
[0493] ##STR58##
[0494] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-thiophen-2-yl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0495] LC/MS: m/z=345 (MH.sup.+)
Example 17
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-3,6-dihydro-2H-pyri-
din-1-yl)-methanone
[0496] ##STR59##
[0497] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-furan-2-yl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0498] LC/MS: m/z=329 (MH.sup.+)
Example 18
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-pyrrol-2-yl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0499] ##STR60##
[0500] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(1H-pyrrol-2-yl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0501] LC/MS: m/z=328 (MH.sup.+)
Example 19
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0502] ##STR61##
[0503] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(1-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine to
provide the title compound in moderate yield.
[0504] LC/MS: m/z=342 (MH.sup.+)
Example 20
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-d-
ihydro-2H-pyridin-1-yl]-methanone
[0505] ##STR62##
[0506] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(1-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine to provide
the title compound in moderate yield.
[0507] LC/MS: m/z=387 (MH.sup.+)
Example 21
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H--
pyridin-1-yl)-methanone
[0508] ##STR63##
[0509] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0510] LC/MS: m/z=398 (MH.sup.+)
[0511] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 22
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-5-phenyl-3,6-dihydro-2H--
pyridin-1-yl)-methanone
[0512] ##STR64##
[0513] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-5-phenyl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0514] LC/MS: In/z=398 (MH.sup.+)
[0515] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 23
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone
[0516] ##STR65##
[0517] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0518] LC/MS: m/z=353 (MH.sup.+)
[0519] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 24
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2'-methyl-3',6'-dihydro-2'H-[2,4-
']bipyridinyl-1'-yl)-methanone
[0520] ##STR66##
[0521] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2'-Methyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl to provide
the title compound in moderate yield.
[0522] LC/MS: m/z=354 (MH.sup.+)
[0523] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 25
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2'-methyl-3',6'-dihydro-2'H-[3,4-
']bipyridinyl-1'-yl)-methanone
[0524] ##STR67##
[0525] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2'-Methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl to provide
the title compound in moderate yield.
[0526] LC/MS: m/z=354 (MH.sup.+)
[0527] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 26
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-3,6-dihydro-2H-[4,4']bi-
pyridinyl-1-yl)-methanone
[0528] ##STR68##
[0529] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-1,2,3,6-tetrahydro-[4,4']bipyridinyl to provide the
title compound in moderate yield.
[0530] LC/MS: m/z 354 (MH.sup.+)
[0531] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 27
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-thiophen-2-yl-3,6-dih-
ydro-2H-pyridin-1-yl)-methanone
[0532] ##STR69##
[0533] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-thiophen-2-yl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0534] LC/MS: m/z=359 (MH.sup.+)
[0535] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 28
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-2-methyl-3,6-dihydr-
o-2H-pyridin-1-yl)-methanone
[0536] ##STR70##
[0537] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-Furan-2-yl-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0538] LC/MS: m/z=343 (MH.sup.+)
[0539] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 29
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-pyrrol-2-yl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0540] ##STR71##
[0541] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-(1H-pyrrol-2-yl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0542] LC/MS: m/z=342 (MH.sup.+)
[0543] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 30
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H--
pyridin-1-yl)-methanone
[0544] ##STR72##
[0545] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0546] LC/MS: m/z=398 (MH.sup.+)
[0547] .sup.1H NMR (CDCl.sub.3) .delta.: 8.83, 8.54, 7.38-7.30,
7.05, 6.12-5.95, 5.03-4.75, 4.21-3.83, 3.02-2.92, 2.44-2.28,
1.33-1.25.
[0548] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 31
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone
[0549] ##STR73##
[0550] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0551] LC/MS: m/z=353 (MH.sup.+)
[0552] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 32
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-d-
ihydro-2H-pyridin-1-yl]-methaone
[0553] ##STR74##
[0554] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-methyl-4-(2-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0555] LC/MS: m/z=443 (MH.sup.+)
[0556] .sup.1H NMR (CDCl.sub.3) .delta.: 8.81, 8.54, 7.90,
7.58-7.30, 7.06, 5.74-5.34, 5.02-4.71, 3.87-3.77, 2.90-2.81,
1.43-1.40.
[0557] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 33
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone
[0558] ##STR75##
[0559] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-methyl-4-(2-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0560] LC/MS: m/z=398 (MH.sup.+)
[0561] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 34
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-d-
ihydro-2H-pyridin-1-yl]-methaone
[0562] ##STR76##
[0563] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-methyl-4-(3-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0564] LC/MS: m/z=443 (MH.sup.+)
[0565] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 35
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-d-
ihydro-2H-pyridin-1-yl]-methaone
[0566] ##STR77##
[0567] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-methyl-4-(4-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0568] LC/MS: m/z=443 (MH.sup.+)
[0569] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 36
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone
[0570] ##STR78##
[0571] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-methyl-4-(3-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0572] LC/MS: m/z=398 (MH.sup.+)
[0573] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 37
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methaone
[0574] ##STR79##
[0575] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-methyl-4-(4-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0576] LC/MS: m/z=398 (MH.sup.+)
[0577] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 38
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-
-pyridin-1-yl]-methanone
[0578] ##STR80##
[0579] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0580] LC/MS: m/z=429 (MH.sup.+)
Example 39
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-
-pyridin-1-yl]-methanone
[0581] ##STR81##
[0582] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0583] LC/MS: m/z=429 (MH.sup.+)
Example 40
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-
-pyridin-1-yl]n-methanone
[0584] ##STR82##
[0585] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0586] LC/MS: m/z=429 (MH.sup.+)
Example 41
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0587] ##STR83##
[0588] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0589] LC/MS: m/z=384 (MH.sup.+)
Example 42
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0590] ##STR84##
[0591] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0592] LC/MS: m/z=384 (MH.sup.+)
Example 43
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0593] ##STR85##
[0594] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0595] LC/MS: m/z=384 (MH.sup.+)
Example 44
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0596] ##STR86##
[0597] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0598] LC/MS: m/z=416 (MH.sup.+)
[0599] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 45
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0600] ##STR87##
[0601] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0602] LC/MS: m/z=416 (MH.sup.+)
[0603] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 46
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0604] ##STR88##
[0605] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Fluoro-phenyl)-2-methyl-1,1,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0606] LC/MS: m/z=416 (MH.sup.+)
[0607] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 47
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0608] ##STR89##
[0609] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0610] LC/MS: m/z=371 (MH.sup.+)
[0611] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 48
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0612] ##STR90##
[0613] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0614] LC/MS: m/z=371 (MH.sup.+)
[0615] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 49
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0616] ##STR91##
[0617] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0618] LC/MS: m/z=371 (MH.sup.+)
[0619] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 50
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0620] ##STR92##
[0621] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0622] LC/MS: m/z=402 (MH.sup.+)
Example 51
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0623] ##STR93##
[0624] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0625] LC/MS: m/z=402 (MH.sup.+)
Example 52
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0626] ##STR94##
[0627] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0628] LC/MS: m/z=402 (MH.sup.+)
Example 53
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0629] ##STR95##
[0630] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0631] LC/MS: m/z=357 (MH.sup.+)
Example 54
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0632] ##STR96##
[0633] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0634] LC/MS: m/z=357 (MH.sup.+)
Example 55
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0635] ##STR97##
[0636] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0637] LC/MS: m/z=357 (MH.sup.+)
Example 56
[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazol-
o[1,5-a]pyrimidin-2-yl)-methanone
[0638] ##STR98##
[0639] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0640] LC/MS: m/z=477 (MH.sup.+)
[0641] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 57
[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazol-
o[1,5-a]pyrimidin-2-yl)-methanone
[0642] ##STR99##
[0643] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0644] LC/MS: m/z=477 (MH.sup.+)
[0645] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 58
[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazol-
o[1,5-a]pyrimidin-2-yl)-methanone
[0646] ##STR100##
[0647] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0648] LC/MS: m/z=477 (MH.sup.+)
[0649] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 59
[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone
[0650] ##STR101##
[0651] In analogy to the procedure described in Example 64,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0652] LC/MS: m/z=432 (MH.sup.+)
[0653] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 60
[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone
[0654] ##STR102##
[0655] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0656] LC/MS: m/z=432 (MH.sup.+)
[0657] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 61
[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazo-
lo[1,5-a]pyrimidin-2-yl)-methanone
[0658] ##STR103##
[0659] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0660] LC/MS: m/z=432 (MH.sup.+)
[0661] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 62
[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]p-
yrimidin-2-yl)-methanone
[0662] ##STR104##
[0663] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0664] LC/MS: m/z=463 (MH.sup.+)
Example 63
[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]p-
yrimidin-2-yl)-methanone
[0665] ##STR105##
[0666] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0667] LC/MS: m/z=463 (MH.sup.+)
Example 64
[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]p-
yrimidin-2-yl)-methanone
[0668] ##STR106##
[0669] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0670] LC/MS: m/z=463 (MH.sup.+)
Example 65
[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone
[0671] ##STR107##
[0672] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0673] LC/MS: m/z=418 (MH.sup.+)
Example 66
[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone
[0674] ##STR108##
[0675] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0676] LC/MS: m/z=418 (MH.sup.+)
Example 67
[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]-
pyrimidin-2-yl)-methanone
[0677] ##STR109##
[0678] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0679] LC/MS: m/z=418 (MH.sup.+)
Example 68
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0680] ##STR110##
[0681] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0682] LC/MS: m/z=432 (MH.sup.+)
[0683] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 69
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0684] ##STR111##
[0685] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0686] LC/MS: m/z=432 (MH.sup.+)
[0687] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 70
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0688] ##STR112##
[0689] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0690] LC/MS: m/z=432 (MH.sup.+)
[0691] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 71
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0692] ##STR113##
[0693] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0694] LC/MS: m/z=388 (MH.sup.+)
[0695] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 72
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0696] ##STR114##
[0697] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0698] LC/MS: m/z=388 (MH.sup.+)
[0699] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 73
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0700] ##STR115##
[0701] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0702] LC/MS: m/z=388 (MH.sup.+)
[0703] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 74
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0704] ##STR116##
[0705] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0706] LC/MS: m/z=418 (MH.sup.+)
Example 75
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0707] ##STR117##
[0708] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0709] LC/MS: m/z=418 (MH.sup.+)
Example 76
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2-
H-pyridin-1-yl]-methanone
[0710] ##STR118##
[0711] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0712] LC/MS: m/z=418 (MH.sup.+)
Example 77
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0713] ##STR119##
[0714] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0715] LC/MS: m/z=374 (MH.sup.+)
Example 78
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0716] ##STR120##
[0717] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0718] LC/MS: m/z=374 (MH.sup.+)
Example 79
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0719] ##STR121##
[0720] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0721] LC/MS: m/z=374 (MH.sup.+)
Example 80
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phe-
nyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone
[0722] ##STR122##
[0723] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-(2-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
to provide the title compound in moderate yield.
[0724] LC/MS: m/z=466 (MH.sup.+)
[0725] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 81
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phe-
nyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone
[0726] ##STR123##
[0727] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
to provide the title compound in moderate yield.
[0728] LC/MS: m/z=466 (MH.sup.+)
[0729] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 82
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phe-
nyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone
[0730] ##STR124##
[0731] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
to provide the title compound in moderate yield.
[0732] LC/MS: m/z=466 (MH.sup.+)
[0733] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 83
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone
[0734] ##STR125##
[0735] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with
2-Methyl-4-(2-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
to provide the title compound in moderate yield.
[0736] LC/MS: m/z=421 (MH.sup.+)
[0737] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 84
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone
[0738] ##STR126##
[0739] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with
2-Methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
to provide the title compound in moderate yield.
[0740] LC/MS: m/z=421 (MH.sup.+)
[0741] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 85
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-ph-
enyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone
[0742] ##STR127##
[0743] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with
2-Methyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
to provide the title compound in moderate yield.
[0744] LC/MS: m/z=421 (MH.sup.+)
[0745] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 86
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0746] ##STR128##
[0747] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0748] LC/MS: m/z=452 (MH.sup.+)
Example 87
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0749] ##STR129##
[0750] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(3-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0751] LC/MS: m/z=452 (MH.sup.+)
Example 88
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6--
dihydro-2H-pyridin-1-yl]-methanone
[0752] ##STR130##
[0753] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0754] LC/MS: m/z=452 (MH.sup.+)
Example 89
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0755] ##STR131##
[0756] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0757] LC/MS: m/z=407 (MH.sup.+)
Example 90
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0758] ##STR132##
[0759] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(3-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0760] LC/MS: m/z=407 (MH.sup.+)
Example 91
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0761] ##STR133##
[0762] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0763] LC/MS: m/z=407 (MH.sup.+)
Example 92
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-
-dihydro-2H-pyridin-1-yl]-methanone
[0764] ##STR134##
[0765] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-(1H-tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0766] LC/MS: m/z=390 (MH.sup.+)
[0767] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 93
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,-
6-dihydro-2H-pyridin-1-yl]-methanone
[0768] ##STR135##
[0769] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-(1H-tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to
provide the title compound in moderate yield.
[0770] LC/MS: m/z=345 (MH.sup.+)
[0771] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 94
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro--
2H-pyridin-1-yl]-methanone
[0772] ##STR136##
[0773] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(1H-Tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0774] LC/MS: m/z=376 (MH.sup.+)
Example 95
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-
-2H-pyridin-1-yl]-methanone
[0775] ##STR137##
[0776] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(1H-Tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to provide
the title compound in moderate yield.
[0777] LC/MS: m/z=331 (MH.sup.+)
Example 96
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone
[0778] ##STR138##
[0779] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to
provide the title compound in moderate yield.
[0780] LC/MS: m/z=355 (MH.sup.+)
[0781] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 97
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dih-
ydro-2H-pyridin-1-yl)-methanone
[0782] ##STR139##
[0783] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to provide
the title compound in moderate yield.
[0784] LC/MS: m/z=400 (MH.sup.+)
[0785] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 98
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone
[0786] ##STR140##
[0787] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the
title compound in moderate yield.
[0788] LC/MS: m/z=341 (MH.sup.+)
Example 99
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-p-
yridin-1-yl)-methanone
[0789] ##STR141##
[0790] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the title
compound in moderate yield.
[0791] LC/MS: m/z=386 (MH.sup.+)
Example 100
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-di-
hydro-2H-pyridin-1-yl)-methanone
[0792] ##STR142##
[0793] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 5-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to
provide the title compound in moderate yield.
[0794] LC/MS: m/z=355 (MH.sup.+)
[0795] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 101
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dih-
ydro-2H-pyridin-1-yl)-methanone
[0796] ##STR143##
[0797] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
5-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to provide
the title compound in moderate yield.
[0798] LC/MS: m/z=400 (MH.sup.+)
[0799] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 102
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H--
pyridin-1-yl)-methanone
[0800] ##STR144##
[0801] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 5-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the
title compound in moderate yield.
[0802] LC/MS: m/z=341 (MH.sup.+)
Example 103
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-p-
yridin-1-yl)-methanone
[0803] ##STR145##
[0804] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
5-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the title
compound in moderate yield.
[0805] LC/MS: m/z=386 (MH.sup.+)
Example 104
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone
[0806] ##STR146##
[0807] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-o-tolyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0808] LC/MS: m/z=412 (MH.sup.+)
[0809] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 105
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone
[0810] ##STR147##
[0811] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-m-tolyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0812] LC/MS: m/z=412 (MH.sup.+)
[0813] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 106
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-
-pyridin-1-yl)-methanone
[0814] ##STR148##
[0815] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
2-Methyl-4-p-tolyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0816] LC/MS: m/z=412 (MH.sup.+)
[0817] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 107
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone
[0818] ##STR149##
[0819] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-o-tolyl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0820] LC/MS: m/z=367 (MH.sup.+)
[0821] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 108
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone
[0822] ##STR150##
[0823] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-m-tolyl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0824] LC/MS: m/z=367 (MH.sup.+)
[0825] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 109
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2-
H-pyridin-1-yl)-methanone
[0826] ##STR151##
[0827] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 2-Methyl-4-p-tolyl-1,2,3,6-tetrahydro-pyridine to provide the
title compound in moderate yield.
[0828] LC/MS: m/z=367 (MH.sup.+)
[0829] The stereo-isomers of this compound are separated. The
S-configurated compound has a different activity than the
R-configurated isomer.
Example 110
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone
[0830] ##STR152##
[0831] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-o-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound
in moderate yield.
[0832] LC/MS: m/z=398 (MH.sup.+)
Example 111
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone
[0833] ##STR153##
[0834] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-m-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound
in moderate yield.
[0835] LC/MS: m/z=398 (MH.sup.+)
Example 112
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin--
1-yl)-methanone
[0836] ##STR154##
[0837] In analogy to the procedure described in Example 1,
6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with
4-p-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound
in moderate yield.
[0838] LC/MS: m/z=398 (MH.sup.+)
Example 113
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone
[0839] ##STR155##
[0840] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-o-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0841] LC/MS: m/z=353 (MH.sup.+)
Example 114
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone
[0842] ##STR156##
[0843] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-m-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0844] LC/MS: m/z=353 (MH.sup.+)
Example 115
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-
-1-yl)-methanone
[0845] ##STR157##
[0846] In analogy to the procedure described in Example 1,
6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted
with 4-p-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title
compound in moderate yield.
[0847] LC/MS: m/z=353 (MH.sup.+)
[0848] The pure stereoisomeric forms (including optical isomers) of
the compounds and the intermediates of this invention may be
obtained by the application of art-known procedures. Diastereomers
may be separated by physical separation methods such as selective
crystallization and chromatographic techniques, e.g. liquid
chromatography using chiral stationary phases. Enantiomers
(optically active isomers) may be separated from each other by
selective crystallization of their diastereomeric salts with
optically active acids. Alternatively, enantiomers may be separated
by chromatographic techniques using chiral stationary phases.
[0849] Said pure stereoisomeric forms may also be derived from the
corresponding pure stereoisomeric form of appropriate starting
materials, provided that the reaction occur stereoselectively.
Stereoisomeric forms of Formula (I) are included within the scope
of this invention.
[0850] For therapeutic use, salts of the compounds of Formula I are
those wherein the counterion is pharmaceutically acceptable.
However, salts of acids and bases, which are non-pharmaceutically
acceptable, may also find use, for example, in the preparation and
purification of pharmaceutically acceptable compounds. All salts
whether pharmaceutically acceptable or not are included within the
ambit of the present invention.
[0851] The pharmaceutically acceptable salts as mentioned above are
meant to comprise the therapeutically active non-toxic salt forms,
which the compounds of formula I are able to form. The latter can
conveniently be obtained by treating the base form with such
appropriate acids as inorganic acids, e.g. hydrohalic acids such as
hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;
phosphoric acid and the like; or organic acids such as acetic,
propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic,
malonic, succinic, maleic, fumaric, malic, tartaric,
2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,
ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,
cyclohexane-sulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic
and the like acids. Conversely, the salt form can be converted by
treatment with alkali into the free base form.
Pharmaceutical Compositions
[0852] The active ingredients of formula (I) of the invention,
together with one or more conventional adjuvants, carriers, or
diluents, may be placed into the form of pharmaceutical
compositions and unit dosages thereof, and in such form may be
employed as solids, such as coated or uncoated tablets or filled
capsules, or liquids, such as solutions, suspensions, emulsions,
elixirs, or capsules filled with the same, all for oral use; in the
form of suppositories or capsules for rectal administration or in
the form of sterile injectable solutions for parenteral (including
intravenous or subcutaneous) use.
[0853] Such pharmaceutical compositions and unit dosage forms
thereof may comprise conventional or new ingredients in
conventional or special proportions, with or without additional
active compounds or principles, and such unit dosage forms may
contain any suitable effective amount of the active ingredient
commensurate with the intended daily dosage range to be employed.
Tablets containing one (1) to one hundred (100) milligrams of
active ingredient or, more broadly, zero point five (0.5) to five
hundred (500) milligrams per tablet, are accordingly suitable
representative unit dosage forms.
[0854] The term "carrier" applied to pharmaceutical compositions of
the invention refers to a diluent, excipient, or vehicle with which
an active compound is administered. Such pharmaceutical carriers
can be sterile liquids, such as water, saline solutions, aqueous
dextrose solutions, aqueous glycerol solutions, and oils, including
those of petroleum, animal, vegetable or synthetic origin, such as
peanut oil, soybean oil, mineral oil, sesame oil and the like. A.
R. Gennaro, 20.sup.th Edition, describes suitable pharmaceutical
carriers in "Remington: The Science and Practice of Pharmacy".
Method of Treating and Pharmaceutical Formulations
[0855] Due to their high degree of activity and their low toxicity,
together presenting a most favorable therapeutic index, the active
principles of formula (I) of the invention may be administered to a
subject, e.g., a living animal (including a human) body, in need
thereof, for the treatment, alleviation, or amelioration,
palliation, or elimination of an indication or condition which is
susceptible thereto, or representatively of an indication or
condition set forth elsewhere in this application, preferably
concurrently, simultaneously, or together with one or more
pharmaceutically-acceptable excipients, carriers, or diluents,
especially and preferably in the form of a pharmaceutical
composition thereof, whether by oral, rectal, or parental
(including intravenous and subcutaneous) or in some cases even
topical route, in an effective amount. Suitable dosage ranges are
1-1000 milligrams daily, preferably 10-500 milligrams daily, and
especially 50-500 milligrams daily, depending 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 the
preference and experience of the physician or veterinarian in
charge.
[0856] The term "therapeutically effective" applied to dose or
amount refers to that quantity of a compound or pharmaceutical
composition that is sufficient to result in a desired activity upon
administration to a living animal body in need thereof.
[0857] The active agents of formula (I) of the present invention
may be administered orally, topically, parenterally, or mucosally
(e.g., buccally, by inhalation, or rectally) in dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers. It is usually desirable to use the oral route.
The active agents may be administered orally in the form of a
capsule, a tablet, or the like (see Remington: The Science and
Practice of Pharmacy, 20.sup.th Edition). The orally administered
medicaments may be administered in the form of a time-controlled
release vehicle, including diffusion-controlled systems, osmotic
devices, dissolution-controlled matrices, and erodible/degradable
matrices.
[0858] For oral administration in the form of a tablet or capsule,
the active drug component of formula (I) may be combined with a
non-toxic, pharmaceutically acceptable excipients such as binding
agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or
hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose,
glucose, mannitol, sorbitol and other reducing and non-reducing
sugars, microcrystalline cellulose, calcium sulfate, or calcium
hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or
silica, steric acid, sodium stearyl fumarate, glyceryl behenate,
calcium stearate, and the like); disintegrants (e.g., potato starch
or sodium starch glycolate); or wetting agents (e.g., sodium lauryl
sulphate), coloring and flavoring agents, gelatin, sweeteners,
natural and synthetic gums (such as acacia, tragacanth or
alginates), buffer salts, carboxymethylcellulose,
polyethyleneglycol, waxes, and the like. For oral administration in
liquid form, the drug components may be combined with non-toxic,
pharmaceutically acceptable inert carriers (e.g., ethanol,
glycerol, water), suspending agents (e.g., sorbitol syrup,
cellulose derivatives or hydrogenated edible fats), emulsifying
agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g.,
almond oil, oily esters, ethyl alcohol or fractionated vegetable
oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or
sorbic acid), and the like. Stabilizing agents such as antioxidants
(BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also
be added to stabilize the dosage forms.
[0859] The tablets containing as active compound a compound of
formula (I) may be coated by methods well known in the art. The
compositions of the invention containing as active compound a
compound of formula (I) may be also introduced in beads,
microspheres or microcapsules, e.g., fabricated from polyglycolic
acid/lactic acid (PGLA). Liquid preparations for oral
administration may take the form of, for example, solutions,
syrups, emulsions or suspensions, or they may be presented as a dry
product for reconstitution with water or other suitable vehicle
before use. Preparations for oral administration may be suitably
formulated to give controlled or postponed release of the active
compound.
[0860] The active drugs of formula (I) may also be administered in
the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles and multilamellar vesicles.
Liposomes can be formed from a variety of phospholipids, such as
cholesterol, stearylamine or phosphatidylcholines, as is well
known.
[0861] Drugs of the invention containing as active compound a
compound of formula (I) may also be delivered by the use of
monoclonal antibodies as individual carriers to which the compound
molecules are coupled. Active drugs may also be coupled with
soluble polymers as targetable drug carriers. Such polymers include
polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl
methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, active drug may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxybutyric acid, polyorthoesters, polyacetals,
polyhydropyrans, polycyanoacrylates, and cross-linked or
amphipathic block copolymers of hydrogels.
[0862] For administration by inhalation, the therapeutics according
to the present invention containing as active compound a compound
of formula (I) may be conveniently delivered in the form of an
aerosol spray presentation from pressurized packs or a nebulizer,
with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas.
In the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount.
Capsules and cartridges of, e.g., gelatin for use in an inhaler or
insufflator can be formulated containing a powder mix of the
compound and a suitable powder base such as lactose or starch.
[0863] The formulations of the invention containing a compound of
formula (I) may be delivered parenterally, i.e., by intravenous
(i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.),
intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or
intradermal (i.d.) administration, by direct injection, via, for
example, bolus injection or continuous infusion. Formulations for
injection can be presented in unit dosage form, e.g., in ampoules
or in multi-dose containers, with an added preservative. The
compositions can take such forms as excipients, suspensions,
solutions, or emulsions in oily or aqueous vehicles, and can
contain formulatory agents such as suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient can be in
powder form for reconstitution with a suitable vehicle, e.g.,
sterile pyrogen-free water, before use.
[0864] Compositions of the present invention containing a compound
of formula (I) may also be formulated for rectal administration,
e.g., as suppositories or retention enemas (e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides).
[0865] The compositions containing a compound of formula (I) may,
if desired, be presented in a pack or dispenser device, which may
contain one or more unit dosage forms containing the active
ingredient and/or may contain different dosage levels to facilitate
dosage titration. The pack may, for example, comprise metal or
plastic foil, such as a blister pack. The pack or dispenser device
may be accompanied by instructions for administration. Compositions
of the invention formulated in a compatible pharmaceutical carrier
may also be prepared, placed in an appropriate container, and
labeled for treatment of an indicated condition.
[0866] As disclosed herein, the dose of the components in the
compositions of the present invention is determined to ensure that
the dose administered continuously or intermittently will not
exceed an amount determined after consideration of the results in
test animals and the individual conditions of a patient. A specific
dose naturally varies depending on the dosage procedure, the
conditions of a patient or a subject animal such as age, body
weight, sex, sensitivity, feed, dosage period, drugs used in
combination, seriousness of the disease. The appropriate dose and
dosage times under certain conditions can be determined by the test
based on the above-described indices but may be refined and
ultimately decided according to the judgment of the practitioner
and each patient's circumstances (age, general condition, severity
of symptoms, sex, etc.) according to standard clinical
techniques.
[0867] Toxicity and therapeutic efficacy of the compositions of the
invention can be determined by standard pharmaceutical procedures
in experimental animals, e.g., by determining the LD.sub.50 (the
dose lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between therapeutic and toxic effects is the therapeutic index and
it may be expressed as the ratio ED.sub.50/LD.sub.50. Compositions
that exhibit large therapeutic indices are preferred.
Examples of Representative Pharmaceutical Compositions
[0868] With the aid of commonly used solvents, auxiliary agents and
carriers, the reaction products can be processed into tablets,
coated tablets, capsules, drip solutions, suppositories, injection
and infusion preparations, and the like and can be therapeutically
applied by the oral, rectal, parenteral, and additional routes.
Representative pharmaceutical compositions containing a compound of
formula (I) according to the present invention follow:
[0869] (a) Tablets suitable for oral administration which contain
the active ingredient, may be prepared by conventional tabletting
techniques.
[0870] (b) For suppositories, any usual suppository base may be
employed for incorporation thereinto by usual procedure of the
active ingredient, such as a polyethyleneglycol which is a solid at
normal room temperature but which melts at or about body
temperature.
[0871] (c) For parental (including intravenous and subcutaneous)
sterile solutions, the active ingredient together with conventional
ingredients in usual amounts are employed, such as for example
sodium chloride and double-distilled water q.s., according to
conventional procedure, such as filtration, aseptic filling into
ampoules or IV-drip bottles, and autoclaving for sterility.
Formulation Examples for the Compounds of Formula (I)
[0872] The following examples are given by way of illustration. As
active ingredient, the compound according to example 1 can be
used.
Example 1
Tablet Formulation
[0873] A suitable formulation for a tablet containing 10 milligrams
of active ingredient is as follows: TABLE-US-00001 mg Active
Ingredient 10 Lactose 61 Microcrystalline Cellulose 25 Talcum 2
Magnesium stearate 1 Colloidal silicon dioxide 1
Example 2
Coated Tablet Formulation
[0874] Another suitable formulation for a tablet containing 100 mg
is as follows: TABLE-US-00002 mg Active Ingredient 100
Polyvinylpyrrolidone, crosslinked 10 Potato starch 20
Polyvinylpyrrolidone 19 Magnesium stearate 1 Microcrystalline
Cellulose 50 Film coated and colored. The film coating material
consists of: Hypromellose 10 Microcryst. Cellulose 5 Talcum 5
Polyethylene glycol 2 Color pigments 5
Example 3
Capsule Formulation
[0875] A suitable formulation for a capsule containing 50
milligrams of active ingredient is as follows: TABLE-US-00003 mg
Active Ingredient 50 Corn starch 26 Dibasic calcium phosphate 50
Talcum 2 Colloidal silicon dioxide 2
[0876] This formulation is filled in a gelatin capsule.
Example 4
Solution for Injection
[0877] A suitable formulation for an injectable solution is as
follows: TABLE-US-00004 Active Ingredient mg 10 Sodium chloride mg
q.s. Water for Injection ml add 1.0
Example 5
Liquid Oral Formulation
[0878] A suitable formulation for 1 liter of an oral solution
containing 2 milligrams of active ingredient in one milliliter of
the mixture is as follows: TABLE-US-00005 mg Active Ingredient 2
Saccharose 250 Glucose 300 Sorbitol 150 Orange flavor 10 Colorant
q.s. Purified water add 1000 ml
Example 6
Liquid Oral Formulation
[0879] Another suitable formulation for 1 liter of a liquid mixture
containing 20 milligrams of active ingredient in one milliliter of
the mixture is as follows: TABLE-US-00006 g Active Ingredient 20.00
Tragacanth 7.00 Glycerol 50.00 Saccharose 400.00 Methylparaben 0.50
Propylparaben 0.05 Black currant-flavor 10.00 Soluble Red color
0.02 Purified water add 1000 ml
Example 7
Liquid Oral Formulation
[0880] Another suitable formulation for 1 liter of a liquid mixture
containing 2 milligrams of active ingredient in one milliliter of
the mixture is as follows: TABLE-US-00007 g Active Ingredient 2
Saccharose 400 Bitter orange peel tincture 20 Sweet orange peel
tincture 15 Purified water add 1000 ml
Example 8
Aerosol Formulation
[0881] 180 g of the aerosol solution contain: TABLE-US-00008 g
Active Ingredient 10 Oleic acid 5 Ethanol 81 Purified Water 9
Tetrafluoroethane 75
[0882] 15 ml of the solution are filled into aluminum aerosol cans,
capped with a dosing valve, purged with 3.0 bar.
Example 9
Trans-Dermal-System formulation
[0883] 100 g of the solution contain: TABLE-US-00009 g Active
Ingredient 10.0 Ethanol 57.5 Propyleneglycol 7.5 Dimethylsulfoxide
5.0 Hydroxyethylcellulose 0.4 Purified water 19.6
[0884] 1.8 ml of the solution is placed on a fleece covered by an
adhesive backing foil. The system is closed by a protective liner
which will be removed before use.
Example 10
Nanoparticle Formulation
[0885] 10 g of polybutylcyanoacrylate nanoparticles contain:
TABLE-US-00010 g Active Ingredient 1.00 Poloxamer 0.10
Butylcyanoacrylate 8.75 Mannitol 0.10 Sodium chloride 0.05
[0886] Polybutylcyanoacrylate nanoparticles are prepared by
emulsion polymerization in a water/0.1 N HCl/ethanol mixture as
polymerization medium. The nanoparticles in the suspension are
finally lyophilized under vacuum.
Example 11
Suspension Formulation
[0887] 1.0 g of the suspension contains the following:
TABLE-US-00011 g Active Ingredient 0.10 Hypromellose 0.01 Purified
water Ad 1.0 g
[0888] Hypromellose is dispersed in water homogeneously with a high
speed mixer/blender. After about one hour of hydration time of the
hypromellose, the active ingredient is blended homogeneously into
the hypromellose solution. The viscosity of the suspension can be
adjusted by the amount of hypromellose, resulting in a very stable
suspension with a very slow tendency of particle sedimentation and
particle agglomeration.
Example 12
Solution for Injection
[0889] 1.0 ml of solution contain: TABLE-US-00012 g Active
Ingredient 0.05 Mannitol q.s. DMSO 0.10 Water for injection Ad 1.0
ml
[0890] The active ingredient is dissolved in DMSO by stirring and
heating (solution 1). The mannitol is dissolved in WFI (solution
2). After cooling down to room temperature solution 1 is mixed with
solution 2 by continuous stirring. The solution is sterilized by
filtration of by autoclaving.
Pharmacology
[0891] The active principles of the present invention, and
pharmaceutical compositions containing them and method of treating
therewith, are characterized by unique and advantageous properties.
The compounds and pharmaceutical compositions thereof exhibit, in
standard accepted reliable test procedures, the following valuable
properties and characteristics
methods
Binding Assays for the Characterization of mGluR5 Antagonists
[0892] [.sup.3H]-MPEP (2-methyl-6-(phenylethynyl)pyridine) binding
to transmembrane allosteric modulatory sites of mGluR5 receptors in
cortical membranes.
Preparation of Rat Cortical Membranes:
[0893] Male Sprague-Dawley rats (200-250 g) are decapitated and
their brains are removed rapidly. The cortex is dissected and
homogenized in 20 volumes of ice-cold 0.32 M sucrose using a
glass-Teflon homogenizer. The homogenate is centrifuged at
1000.times.g for 10 minutes. The pellet is discarded and the
supernatant centrifuged at 20,000.times.g for 20 minutes. The
resulting pellet is re-suspended in 20 volumes of distilled water
and centrifuged for 20 minutes at 8000.times.g. Then the
supernatant and the buffy coat are centrifuged at 48,000.times.g
for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. The
pellet is then re-suspended and centrifuged two to three more times
at 48,000.times.g for 20 minutes in the presence of 50 mM Tris-HCl,
pH 8.0. All centrifugation steps are carried out at 4.degree. C.
After resuspension in 5 volumes of 50 mM Tris-HCl, pH 8.0 the
membrane suspension is frozen rapidly at -80.degree. C.
[0894] On the day of assay the membranes are thawed and washed four
times by resuspension in 50 mM Tris-HCl, pH 8.0 and centrifugation
at 48,000.times.g for 20 minutes and finally re-suspended in 50 mM
Tris-HCl, pH 7.4. The amount of protein in the final membrane
preparation (500-700 .mu.g/ml) is determined according to the
method of Lowry (Lowry 0. H. et al. 1951. J. Biol. Chem. 193,
256-275).
[.sup.3H]-MPEP Assay
[0895] Incubations are started by adding [.sup.3H]-MPEP (50.2
Ci/mmol, 5 nM, Tocris, GB) to vials with 125-250 .mu.g protein
(total volume 0.25 ml) and various concentrations of the agents.
Alternatively, assays are performed with [.sup.3H]-MMPEP
(2-(3-methoxyphenylethynyl)-6-methylpyridine hydrochloride) as
radioligand. The incubations are continued at room temperature for
60 minutes (equilibrium is achieved under the conditions used).
Non-specific binding is defined by the addition of unlabeled MPEP
(10 .mu.M). Incubations are terminated using a Millipore filter
system. The samples are rinsed twice with 4 ml of ice-cold assay
buffer over glass fibre filters (Schleicher & Schuell, Germany)
under a constant vacuum. Following separation and rinse, the
filters are placed into scintillation liquid (5 ml Ultima Gold,
Perkin Elmer, Germany) and radioactivity retained on the filters is
determined with a conventional liquid scintillation counter
(Canberra Packard, Germany).
Characterization:
[0896] Specific binding is extremely high i.e. normally >85% and
essentially independent of buffer (Tris or HEPES both 50 mM) and pH
(6.8-8.9). There is a clear saturable protein dependence and the
chosen protein concentration used for subsequent assays (500-700
.mu.g/ml) is within the linear portion of this dependence. Cold
MPEP displaces hot ligand with an IC.sub.50 of 11.2.+-.0.64 nM. The
K.sub.d of [.sup.3H]-MPEP of 13.6 nM is determined by Scatchard
analysis and used according to the Cheng Prussoff relationship to
calculate the affinity of displacers as K.sub.d values (IC.sub.50
of cold MPEP equates to a K.sub.i of 8.2 nM). B.sub.max is 0.56
pm/mg protein.
Functional Assays of mGluR5 Receptors
Cytosolic Calcium Studies with Stably Transfected Cells
[0897] Chinese hamster ovary cells (CHO-K1 cells), stably
transfected for inducible expression of a human metabotropic
glutamate receptor mGluR5, are seeded into black clear bottom 96
well plates at a density of 35.000 cells per well. The standard
growth medium used (Dulbecco's modified Eagle Medium, DMEM plus
L-proline) contains the appropriate inducer
isopropyl-.beta.-D-thiogalactopyranosid (IPTG) to achieve optimal
receptor expression. One day after seeding the growth medium is
exchanged for reconstituted Ca-Kit (Molecular Devices, USA) and
incubated for one hour. Ca-Kit is reconstituted in an assay buffer
containing 20 mM HEPES pH 7.4, glutamic-pyruvate transaminase,
pyridoxal phosphate and sodium pyruvate in Hank's balanced salt
solution (HBBS). Agonistic compounds to the receptor elicit
increases in cytosolic calcium which can be measured as increases
in fluorescence signals by use of a fluorescence imaging plate
reader (Molecular Devices). To analyze their potency to modulate
the Ca-response test compounds, dissolved in a final DMSO
concentration of 0.5%, are added on-line 5 minutes before the
agonist to the receptor (L-quisqualic acid at a concentration
giving .about.80% of the maximal signal).
Astrocyte Culture:
[0898] Primary astrocyte cultures are prepared from cortices of
newborn rats as described by Booher and Sensenbrenner (1972,
Neurobiology 2(3):97-105). Briefly, Sprague-Dawley rat pups (2-4 d
old) are decapitated and neocortices are dissected, disintegrated
with a nylon filter (pore size 80 .mu.m) and carefully triturated.
The cell suspension is plated on poly-D-lysine pre-coated flasks
(Costar, Netherlands) and cultivated in Dulbecco's Modified Eagle's
Medium (DMEM, Invitrogen, Germany) supplemented with 10% foetal
calf serum (FCS, Sigma, Germany), 4 mM glutamine and 50 .mu.g/ml
gentamycin (both Biochrom, Germany) at 37.degree. C. in a
humidified atmosphere of 5% CO.sub.2/95% air for 7 d with
exchanging the medium at day 2 and 6.
[0899] After 7 days in vitro (DIV), cells are shaken overnight at
250 rpm to remove oligodendrocytes and microglia. The next day,
astrocytes are rinsed twice with CMF-PBS (calcium- and
magnesium-free phosphate buffered saline, Biochrom, Germany),
trypsinized and subplated on poly-D-lysine pre-coated 96-well
plates (Greiner, Germany) at a density of 40,000 cells/well. 24 h
after establishing the secondary culture the astrocytes are rinsed
with PBS.sup.++ (phosphate buffered saline, Biochrom, Germany) and
fed with astrocyte-defined medium (ADM) consisting of DMEM
containing 1.times. G5-supplement (Invitrogen, Germany), 0.5
.mu.g/ml heparan sulfate, and 1.5 .mu.g/ml fibronectin (both Sigma,
Germany) (Miller et al., (1993) Brain Res. 618(1):175-8). 3 d later
the medium is exchanged and the cells incubated for another 2-3 d,
so that at the time of experiments astrocytes are 14-15 DIV.
Immunocytochemistry
[0900] Immunostaining is performed to confirm the presence of
astrocytic markers such as the glial fibrillary acidic protein
(GFAP) as well as to monitor the expression of mGluR5
receptors.
[0901] Cytosolic Calcium Studies with Astrocytes:
[0902] The increase of cytosolic calcium after stimulation with the
mGluR5 agonist L-quisqualate is measured using a fluorometric
imaging plate reader (FLIPR) and the Ca-Kit (both Molecular
Devices). Prior to addition of agonist or antagonist the medium is
aspirated and cells are loaded for 2 h at RT with 150 .mu.l of
loading buffer consisting of Ca-sensitive dye reconstituted in
sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium
chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM),
and HEPES (20 mM), pH 7.3. Subsequently, plates are transferred to
FLIPR to detect calcium increase with the addition of L-quisqualate
(100 nM) measured as relative fluorescence units (RFU). If
antagonists are tested, these compounds are pre-incubated for 10
minutes at RT before addition of the respective agonist.
[0903] For positive modulators, concentration-response curves for
quisqualate are performed in the presence and absence of 10 .mu.M
modulator to determine the extent of potentiation/agonist potency
increase. Thereafter, concentration-response curves for the
positive modulator are performed in the presence of a fixed
concentration of quisqualate showing the biggest window for
potentiation (normally 10-30 nM).
Data Analysis
[0904] The fluorescence signal increase after addition of agonist
reflects the increase of cytosolic calcium. Inconsistencies in the
amount of cells per well are normalized by using the spatial
uniformity correction of the FLIPR software. The mean of replicated
temporal data (n=3-5) is calculated and used for graphical
representation. For the evaluation of the pharmacology, the calcium
changes in response to different concentrations of agonist or
antagonist are determined using a maximum minus minimum (MaxMin)
calculation.
[0905] All responses (RFU-values) are determined as percentage of
control (=maximum response). EC.sub.50 and IC.sub.50 are calculated
according the logistic equation using GraFit 5.0 (Erithacus
Software, GB) or Prism 4.0 (GraphPad Software, USA). The compounds
of the present invention have a potency (IC.sub.50) within a range
of about 0.5 nM to about 100 .mu.M.
[0906] Results for representative compounds of the invention are
shown in Tables A1-A3.
[0907] In conclusion, from the foregoing, it is apparent that the
present invention provides novel and valuable applications and uses
of the compounds of the present invention, which compounds comprise
the active principle according to the present invention, as well as
novel pharmaceutical compositions thereof and methods of
preparation thereof and of treating therewith.
[0908] The high order of activity of the active agent of the
present invention and compositions thereof, as evidenced by the
tests reported, is indicative of utility based on its valuable
activity in human beings as well as in lower animals. Clinical
evaluation in human beings has not been completed. It will be
clearly understood that the distribution and marketing of any
compound or composition falling within the scope of the present
invention for use in human beings will of course have to be
predicated upon prior approval by governmental agencies which are
responsible for and authorized to pass judgment on such
questions.
[0909] The instant compounds of formula (I) represent a novel class
of mGluR5 modulators. In view of their potency, they will be useful
therapeutics in a wide range of disorders, in particular CNS
disorders, which involve excessive glutamate induced
excitation.
[0910] These compounds accordingly find application in the
treatment of the disorders of a living animal body, especially a
human, as listed earlier in the description.
[0911] These compounds also find application in the treatment of
indications in a living animal body, especially a human, wherein a
particular condition does not necessarily exist but wherein a
particular physiological parameter may be improved through
administration of the instant compounds, including cognitive
enhancement.
[0912] Neuroprotection as well as cognitive enhancement can also be
achieved by combining application of these compounds with NMDA
receptor antagonists like Memantine and Neramexane.
[0913] The method-of-treating a living animal body with a compound
of the invention, for the inhibition of progression or alleviation
of the selected ailment therein, is as previously stated by any
normally-accepted pharmaceutical route, employing the selected
dosage which is effective in the alleviation of the particular
ailment desired to be alleviated. Use of the compounds of the
present invention in the manufacture of a medicament for the
treatment of a living animal for inhibition of progression or
alleviation of selected ailments or conditions, particularly
ailments or conditions susceptible to treatment with a Group I
mGluR modulator is carried out in the usual manner comprising the
step of admixing an effective amount of a compound of the invention
with a pharmaceutically-acceptable diluent, excipient, or carrier,
and the method-of-treating, pharmaceutical compositions, and use of
a compound of the present invention in the manufacture of a
medicament.
[0914] Representative pharmaceutical compositions prepared by
admixing the active ingredient with a suitable
pharmaceutically-acceptable excipient, diluent, or carrier, include
tablets, capsules, solutions for injection, liquid oral
formulations, aerosol formulations, TDS formulations, and
nanoparticle formulations, thus to produce medicaments for oral,
injectable, or dermal use, also in accord with the foregoing.
TABLE-US-00013 TABLE A1 (Cytosolic Calcium studies with stably
transfected cells) Compound Chemical Name
mGluR5_FLIPR_h_CHONAM_IC50 [.mu.M] ##STR158##
6-bromo-2-[(4-phenyl-3,6- dihydro-1(2H)-
pyridinyl)carbonyl]pyrazolo[1,5- a]pyrimidine; Example 1 0.4930
[0915] TABLE-US-00014 TABLE A2 (Astrocyte culture test)
mGluR5_FLIPR_r_rpA Compound Chemical Name IC50 [.mu.M] ##STR159##
6-bromo-2-[(4-phenyl-3,6-dihydro- 1(2H)-
pyridinyl)carbonyl]pyrazolo[1,5- a]pyrimidine; Example 1 0.08
[0916] TABLE-US-00015 TABLE A3 (.sup.3H-MPEP Assay) mGluR5_MPEP
Compound Chemical Name rCTX_IC50 [.mu.M] ##STR160##
6-bromo-2-[(4-phenyl-3,6-dihydro- 1(2H)-pyridinyl)carbonyl]-
pyrazolo[1,5-a]pyrimidine; Example 1 0.25
* * * * *