U.S. patent application number 10/482764 was filed with the patent office on 2004-12-09 for novel heteroaryl derivatives, their preparation and use.
Invention is credited to Andersen, Kim, Krog-Jensen, Christian, Mikkelsen, Ivan, Moltzen, Ejner K., Rottlander, Mario, Ruhland, Thomas.
Application Number | 20040248883 10/482764 |
Document ID | / |
Family ID | 8160598 |
Filed Date | 2004-12-09 |
United States Patent
Application |
20040248883 |
Kind Code |
A1 |
Rottlander, Mario ; et
al. |
December 9, 2004 |
Novel heteroaryl derivatives, their preparation and use
Abstract
A heteroaryl derivative having the formula (I). The compounds of
the invention are considered useful for the treatment of affective
disorders such as general anxiety disorder, panic disorder,
obsessive compulsive disorder, depression, social phobia and eating
disorders, and neurological disorders such as psychosis. 1
Inventors: |
Rottlander, Mario; (Valby,
DK) ; Moltzen, Ejner K.; (Gentofte, DK) ;
Mikkelsen, Ivan; (Koge, DK) ; Ruhland, Thomas;
(Roskilde, DK) ; Andersen, Kim; (Ridgewood,
NJ) ; Krog-Jensen, Christian; (Rungsted Kyst,
DK) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Family ID: |
8160598 |
Appl. No.: |
10/482764 |
Filed: |
July 6, 2004 |
PCT Filed: |
June 27, 2002 |
PCT NO: |
PCT/DK02/00435 |
Current U.S.
Class: |
514/218 ;
514/252.19; 514/253.09; 540/575; 544/295; 544/360 |
Current CPC
Class: |
C07D 413/12 20130101;
A61P 25/04 20180101; A61P 25/22 20180101; A61P 43/00 20180101; A61P
9/00 20180101; A61P 25/00 20180101; C07D 405/12 20130101; A61P 9/10
20180101; A61P 25/06 20180101; A61P 25/32 20180101; C07D 409/14
20130101; A61P 25/24 20180101; A61P 25/28 20180101; C07D 401/12
20130101; A61P 25/18 20180101; A61P 1/14 20180101 |
Class at
Publication: |
514/218 ;
514/252.19; 514/253.09; 540/575; 544/295; 544/360 |
International
Class: |
A61K 031/551; A61K
031/496; C07D 43/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2001 |
PA |
2001 01036 |
Claims
1. 5wherein X represents O, NR.sup.16, S or CR.sup.4R.sup.5. Y is
--CR.sup.6R.sup.7--, --CR.sup.6R.sup.7--CR.sup.8R.sup.9--,
--CR.sup.6.dbd.CR.sup.7-- or CO--CR.sup.6R.sup.7; or X and Y
together form a group --CR.sup.4.dbd.CR.sup.5-- or
--CR.sup.4.dbd.CR.sup.5--CR.sup- .6R.sup.7--; Z represents O or S;
n is 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 2 or 3: A is O or S; W is
N, C or CH; Q is N, C or CH; wherein the dotted line means an
optional bond; R.sup.1-R.sup.9 are each independently selected from
hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
aryl-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylthio,
hydroxy, formyl, acyl, amino, C.sub.1-6-alkylamino,
di(C.sub.1-6-alkyl)amino, acylamino, C.sub.1-6-alkoxycarbonylamino,
aminocarbonylamino, C.sub.1-6-alkylaminocarbonylamino and
di(C.sub.1-6-alkyl)aminocarbonylami- no; and R.sup.16 is selected
from hydrogen, halogen, nitro, cyano, trifluoromethyl,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
aryl-C.sub.1-6-alkyl, formyl, acyl; and R.sup.10 and R.sup.11 are
each independently selected from hydrogen and C.sub.1-6-alkyl or
may together form a bridge consisting of two or three methylene
groups; and R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently selected from hydrogen, halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, aryl, heteroaryl,
C.sub.1-6-alkoxy, C.sub.1-6-alkylthio, C.sub.1-6-alkylsulphonyl,
hydroxy, formyl, acyl, amino, acylamino, aminocarbonyl,
C.sub.1-6-alkoxycarbonylamino, aminocarbonylamino,
C.sub.1-6-alkylaminocarbonylamino,
di(C.sub.1-6-alkyl)aminocarbonylamino, SO.sub.2NR.sup.20R.sup.21
and NR.sup.20R.sup.21 wherein R.sup.20 and R.sup.21 independently
represent hydrogen, C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl or
phenyl; or R.sup.20 and R.sup.21 together with the nitrogen to
which they are attached form a 5- or 6-membered ring optionally
containing one further heteroatom, which ring may optionally be
substituted by C.sub.1-6-alkyl or acyl; any of its enantiomers or
any mixture thereof, or an acid addition salt thereof.
2. A compound of claim 1, characterised in that Z is --O--.
3. A compound of claim 1, characterised in that Y is
--CR.sup.6R.sup.7 or Y is --CH.sub.2CO--.
4. A compound of claim 1, characterised in that X is O or NH.
5. A compound of claim 1, characterised in that W is N.
6. A compound of claim 1, characterised in that n is 2, 3 or 4.
7. A compound of claim 6, characterised in that n is 2.
8. A compound of claim 1, characterised in that R.sup.1, R.sup.2
and R.sup.3 are independently representing hydrogen, halogen or
CN.
9. A compound of claim 1, characterised in that R.sup.12, R.sup.13,
R.sup.14 and R.sup.15 are independently selected from the group
consisting of hydrogen, halogen, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.1-6-alkoxy, cyano,
C.sub.1-6-alkylsulphonyl, acyl, nitro, trifluoromethyl and
trifluoromethoxy.
10. A compound of claim 1, characterised in that R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are independently selected from a
group consisting of hydrogen, heteroaryl, trifluoromethyl, cyano,
C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl, halogen, NR.sup.20R.sup.21,
SO.sub.2NR.sup.20R.sup.- 21, aryl, C.sub.1-6-alkylsulfonyl
aminocarbonyl and acylamino.
11. A compound of claim 10, characterised in that R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are independently selected from the
group consisting of hydrogen, thiophen, trifluoromethyl, cyano,
methyl, ethyl, cyclopropyl, chloro, bromo, fluoro, piperazinyl,
1-piperidinyl, 1-piperidinyl-sulfonyl, methanesulfonyl,
methylsulfidyl, phenyl aminocarbonyl and acylamino.
12. The compound according to claim 1 which is
2-{2-[4-(2,3-Dihydrobenzo[1-
,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile,
1a
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-
-methyl-4-trifluoromethylnicotinonitrile, 1b
2-{2-[4-(8-Cyano-2,3-dihydrob-
enzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methyl-4-trifluoromet-
hylnicotinonitrile, 1c
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethylsulfanyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile,
1d
{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsu-
lfanyl}-6-methylnicotinonitrile, 1e
3-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-
-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1f
2-Chloro-3-{2-[4-(2,3-dihy-
drobenzo[1,4]dioxin-5-yl)piperazin-1-yl] ethoxy} pyridine, 1g
2-Bromo-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}p-
yridine, 1h
3-Chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-
-yl] ethoxy}pyridine, 1i
2-Chloro-3-{2-[4-(8-cyano-2,3-Dihydrobenzo[1,4]di-
oxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 1j
2-Bromo-3-{2-[4-(8-Cyano-2,3--
Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 1k
3-Chloro-5-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl-
]ethoxy}pyridine, 1l
3-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)pip-
erazin-1-yl]ethoxy}-2-methylpyridine, 1m
4-{2-[4-(8-Cyano-2,3-dihydrobenzo-
[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-3-(piperidin-1-ylsulfonyl)p-
yridine, 1n
4-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethyl-
sulfanyl}-3-(piperidin-1-ylsulfonyl)pyridine, 1o
2-{4-[4-(2,3-Dihydrobenzo-
[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine,
1p
2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butyl-
sulfanyl}-5-trifluoromethylpyridine 1q
2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1-
,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine,
1r
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulfanyl}--
5-trifluoromethylpyridine, 1s
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)pi-
perazin-1-yl]propylsulfanyl}-4,6-dimethyl-nicotinonitrile, 1t
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-4-
,6-dimethyl-nicotinonitrile, 1u
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]diox-
in-5-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine,
1v
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsu-
lfanyl}-4,6-dimethylnicotinonitrile, 1x
2-{2-[4-(2,3-Dihydrobenzo[1,4]diox-
in-5-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2a
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsul-
fanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2b
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsul-
fanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2c
2-{2-[4-(8-Cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsul-
fanyl}-6-methylnicotinamide, 2d
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]diox- in-5-yl)piperazin
1-yl]ethylsulfanyl}nicotinonitrile, 2e
4-Cyano-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}p-
yridine, 2f
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethox-
y}-6-methylnicotinamide, 2g
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)pipe-
razin-1-yl]ethoxy)-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2h
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4-methyl-
-6-(4-methylpiperazin-1-yl)nicotinonitrile, 2i
6-Cyclopropyl-2-{2-[4-(2,3--
dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4-trifluoromethylnicot-
inonitrile, 2j
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hoxy}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2k
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-
,6-dimethyl-3-phenylsulfonylpyridine, 2l
2-{2-[4-(8-Cyano-2,3-dihydrobenzo-
[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}pyridine, 2m
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-
,6-dimethylnicotinonitrile, 2n
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]diox-
in-5-yl)piperazin-1-yl]ethylsulfanyl}-4-methylnicotinonitrile, 2o
5-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsu-
lfanyl}nicotinonitrile, 2p
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-
-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2q
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsu-
lfanyl}-5-fluoronicotinonitrile, 2r
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]-
dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile,
2s
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl-
]ethylsulfanyl}-4-methylnicotinonitrile, 2t
5-Chloro-2-{3-[4-(8-cyano-2,3--
dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnic-
otinonitrile, 2u
5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-S-y-
l)piperazin-1-yl]ethylsulfanyl} nicotinonitrile, 2v
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl-
]ethylsulfanyl}nicotinonitrile, 2x
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobe-
nzo[1,4]dioxin-S-yl)piperazin-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile,
2y
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]-
ethylsulfanyl]nicotinonitrile, 2z
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzox-
azin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile,
2aa
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piper-
azin-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2ab
4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-
-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ac
5-Chloro-2-[2-[4-(6-chlo-
ro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6--
dimethylnicotinonitrile, 2ad
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-be-
nzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile,
2ae
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-
-1-yl]ethylsulfanyl]nicotinonitrile, 2af
6-Chloro-2-[2-[4-(6-chloro-2,3-di-
hydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-5-fluoronicot-
inonitrile, 2ag
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]nicotinonitrile, 2ah
2-[2-[4-(6-Chloro-2,3-dihydro-1,-
4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitril-
e, 2ai
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2aj
4-Chloro-2-[2-[4-(6-chl-
oro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-6-methyl-
nicotinonitrile, 2ak
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-
-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile,
2al
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl-
]ethylsulfanyl]nicotinonitrile, 2am
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-
-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile,
2an
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl-
]ethylsulfanyl]-5-fluoronicotinonitrile, 2ao
5-Cyano-4-{2-[4-(2,3-dihydrob-
enzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2ap
5-Cyano-4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsul-
fanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2aq
5-Cyano-4-{2-[4-(8-cyano-2-
,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine,
2ar
5-Cyano-4-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-
-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2 as
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-
,6-dimethylpyrimidine, 2 at
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-
-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylpyrimidine, 2au
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-
-methoxynicotinonitrile, 2av
6-Chloro-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-
-5-yl)piperazin-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2ax
6-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl-
]ethylsulfanyl}-5-fluoronicotinonitrile, 2ay
2-{2-[4-(2,3-Dihydrobenzo[1,4-
]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-5-ethylpyrimidine, 2az
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-
-trifluoromethylpyrimidine, 2ba
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)-
piperazin-1-yl]ethylsulfanyl}-4,6-dimethoxypyrimidine, 2bb
4-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl-
]ethylsulfanyl}-6-methylpyrimidine, 2bc
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[-
1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine,
2bd or an acid addition salt thereof.
13. A pharmaceutical composition comprising at least one compound
of Formula I according to claim 1, or a pharmaceutically acceptable
acid addition salt thereof or prodrug thereof in a therapeutically
effective amount and in combination with one or more
pharmaceutically acceptable carriers or diluents.
14. (Cancelled)
15. (Cancelled)
16. (Cancelled)
17. A method for the treatment of a disorder or disease of living
animal body, which is responsive to the effect of inhibition of
serotonin uptake and antagonism of 5-HT.sub.1A receptors comprising
administering to a living animal body, a therapeutically effective
amount of a compound according to claim 1 or a pharmaceutically
acceptable acid addition salt thereof.
18. A method for the treatment of a disorder or disease of living
animal body, which is responsive to the effect of 5-HT.sub.1A and
D.sub.4 receptors comprising administering to a living animal body,
a therapeutically effective amount of a compound according to claim
1 or a pharmaceutically acceptable acid addition salt thereof.
19. A method of treatment according to claim 1 where the disorder
or disease is an affective disorder or a neurological disorder.
20. The method of treatment according to claim 19, where the
affective disorder is general anxiety disorder, panic disorder,
obsessive compulsive disorder, depression, social phobia or an
eating disorder.
21. The method of treatment according to claim 19, where the
neurological disorder is psychosis.
22. The method of treatment according to claim 17, wherein the
living animal is a human.
23. The method of treatment according to claim 18, wherein the
living animal is a human.
Description
[0001] The present invention relates to novel heteroaryl
derivatives potently binding to the 5-HT.sub.1A receptor,
pharmaceutical compositions containing these compounds and the use
thereof for the treatment of certain psychiatric and neurological
disorders. Many of the compounds of the invention have also potent
serotonin reuptake inhibition activity and are thus considered
particularly useful for the treatment of depression.
[0002] Furthermore, many compounds of the invention have also
effect at dopamine D.sub.3 and D.sub.4 receptors and are considered
to be useful for the treatment of psychosis.
BACKGROUND ART
[0003] Clinical and pharmacological studies have shown that
5-HT.sub.1A agonists and partial agonists are useful in the
treatment of a range of affective disorders such as generalised
anxiety disorder, panic disorder, obsessive compulsive disorder,
depression and aggression.
[0004] It has also been reported that 5-HT.sub.1A ligands may be
useful in the treatment of ischaemia
[0005] An overview of 5-HT.sub.1A antagonists and proposed
potential therapeutic targets for these antagonists based upon
preclinical and clinical data are presented by Schechter et al.,
Serotonin 1997, Vol.2, Issue 7. It is stated that 5-HT.sub.1A
antagonists may be useful in the treatment of schizophrenia, senile
dementia, dementia associated with Alzheimer's disease, and in
combination with SSR1 antidepressants also to be useful in the
treatment of depression.
[0006] 5-HT reuptake inhibitors are well-known antidepressant drugs
and useful for the treatment of panic disorders and social
phobia
[0007] The effect of combined administration of a compound that
inhibits serotonin reuptake and a 5-HT.sub.1A receptor antagonist
has been evaluated in several studies (Innis, R. B. et al. Eur. J.
Pharmacol. 1987, 143, p 195-204 and Gartside, S. E., Br. J.
Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al. Trends
Pharmacol. Sci. 1994, 15, 220). In these studies it was found that
combined 5-HT.sub.1A receptor antagonists and serotonin reuptake
inhibitors would produce a more rapid onset of therapeutic
action.
[0008] Dopamine D.sub.4 receptors belong to the family of dopamine
D.sub.2-like receptors which is considered to be responsible for
the antipsychotic effects of neuroleptics. Doparine D.sub.4
receptors are primarily located in areas of the brain other than
striatum, suggesting that dopamine D.sub.4 receptor ligands have
antipsychotic effect and are devoid of extrapyramidal activity.
[0009] Accordingly, dopamine D.sub.4 receptor ligands are potential
drugs for the treatment of psychosis and positive symptoms of
schizophrenia and compounds with combined effects at dopamine
D.sub.4, and serotonergic receptors may have the further benefit of
improved effect on negative symptoms of schizophrenia, such as
anxiety and depression, alcohol abuse, impulse control disorders,
aggression, side effects induced by conventional antipsychotic
agents, ischaemic disease states, migraine, senile dementia and
cardiovascular disorders and in the improvement of sleep.
[0010] Dopamine D.sub.3 receptors also belong to the family of
dopamine D.sub.2 like receptors. D.sub.3 antagonistic properties of
an antipsychotic drug could reduce the negative symptoms and
cognitive deficits and result in an improved side effect profile
with respect to EPS and hormonal changes.
[0011] Accordingly, agents acting on the 5-HT.sub.1A receptor, both
agonists and antagonists, are believed to be of potential use in
the therapy of psychiatric and neurological disorders and thus
being highly desired. Furthermore, antagonists at the same time
having potent serotonin reuptake inhibition activity and/or D.sub.4
and/or D.sub.3 activity may be particularly useful for the
treatment of various psychiatric and neurological diseases.
[0012] Bart J van Steen et al. J. Med. Chem. 1994, 37(17), 2761-73
describes certain related benzofuran and benzodioxan derivatives
having affinity for the 5SHT.sub.1A receptor and therefore being
useful in the treatment of depression and anxiety.
SUMMARY OF THE INVENTION
[0013] It has now been found that compounds of a certain class of
heteroaryl derivatives bind to the 5-HT.sub.1A receptor with high
affinities. Additionally, the compounds also show serotonin
reuptake inhibition activity. Furthermore, it has been found that
many of the compounds have effect at dopamine D.sub.3 and/or
D.sub.4 receptors.
[0014] Accordingly, the present invention relates to novel
compounds of the general Formula I: 2
[0015] wherein
[0016] X represents O, NR.sup.16, S or CR.sup.4R.sup.5.
[0017] Y is --CR.sup.6R.sup.7--,
--CR.sup.6R.sup.7--CR.sup.8R.sup.9--, --CR.sup.6.dbd.CR.sup.7-- or
CO--CR.sup.6R.sup.7; or
[0018] X and Y together form a group --CR.sup.4.dbd.CR.sup.5-- or
--CR.sup.4.dbd.CR.sup.5--CR.sup.6R.sup.7--;
[0019] Z represents O or S;
[0020] n is 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0021] m is 2 or 3:
[0022] A is O or S;
[0023] W is N, C or CH;
[0024] Q is N, C or CH;
[0025] wherein the dotted line means an optional bond;
[0026] R.sup.1-R.sup.9 are each independently selected from
hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
aryl-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylthio,
hydroxy, formyl, acyl, amino, C.sub.1-6-alkylamino,
di(C.sub.1-6-alkyl)amino, acylamino, C.sub.1-6-alkoxycarbonylamino,
aminocarbonylamino, C.sub.1-6-alkylamiocarbonylamino and
di(C.sub.1-6-alkyl)aminocarbonylamin- o; and
[0027] R.sup.16 is selected from hydrogen, halogen, nitro, cyano,
trifluoromethyl, C.sub.1-6-alyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloallyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, aryl-C.sub.1-6-alkyl, formyl,
acyl; and
[0028] R.sup.10 and R.sup.11 are each independently selected from
hydrogen and C.sub.1-6-alkyl or may together form a bridge
consisting of two or three methylene groups; and
[0029] R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently selected from hydrogen, halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, aryl, heteroaryl,
C.sub.1-6-alkoxy, C.sub.1-6-alkylthio, C.sub.1-6-alkylsulphonyl,
hydroxy, formyl, acyl, amino, acylamino, aminocarbonyl,
C.sub.1-6-alkoxycarbonylamino, aminocarbonylamino,
C.sub.1-6-alkylaminocarbonylamino,
di(C.sub.1-6-alkyl)aminocarbonylamino, SO.sub.2NR.sup.20R.sup.21
and NR.sup.20R.sup.21 wherein R.sup.20 and R.sup.21 independently
represent hydrogen, C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl or
phenyl; or R.sup.20 and R.sup.21 together with the nitrogen to
which they are attached form a 5- or 6-membered ring optionally
containing one further heteroatom, which ring may optionally be
substituted by C.sub.1-6-alkyl or acyl;
[0030] any of its enantiomers or any mixture thereof, or an acid
addition salt thereof.
[0031] The invention also relates to a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof and at least one pharmaceutically
acceptable carrier or diluent.
[0032] In a further embodiment, the invention relates to the use of
a compound of formula (I) or a pharmaceutically acceptable acid
addition salt thereof for the preparation of a medicament for the
treatment of a disorder or disease responsive to the inhibition of
serotonin uptake and antagonism of 5-HT.sub.1A receptors.
[0033] In a further embodiment, the invention relates to the use of
a compound of formula (I) or a pharmaceutically acceptable acid
addition salt thereof for the preparation of a medicament for the
treatment of a disorder or disease responsive to the combined
effect of 5-HT.sub.1A receptors and dopamine D.sub.4 receptors.
[0034] In particular, the invention relates to the use of a
compound according to the invention or a pharmaceutically
acceptable acid addition salt thereof for the preparation of a
medicament for the treatment of affective disorders such as general
anxiety disorder, panic disorder, obsessive compulsive disorder,
depression, social phobia and eating disorders; other psychiatric
disorders such as psychosis and neurological disorders.
[0035] In still another embodiment, the present invention relates
to a method for the treatment of a disorder or disease of living
animal body, including a human, which is responsive to the
inhibition of serotonin uptake and antagonism of 5-HT.sub.1A
receptors comprising administering to such a living animal body,
including a human, a therapeutically effective amount of a compound
of formula (I) or a pharmaceutically acceptable acid addition salt
thereof.
[0036] In still another embodiment, the present invention relates
to a method for the treatment of a disorder or disease of living
animal body, including a human, which is responsive to the effect
of 5-HT.sub.1A and D.sub.4 receptors comprising administering to
such a living animal body, including a human, a therapeutically
effective amount of a compound of formula (1) or a pharmaceutically
acceptable acid addition salt thereof.
[0037] Due to their combined antagonism of 5-HT.sub.1A receptors
and serotonin reuptake inhibiting effect, the compounds of the
invention are considered particularly useful as fast onset of
action medicaments for the treatment of depression. The compounds
may also be useful for the treatment of depression in patients who
are resistant to treatment with currently available
antidepressants.
[0038] The compounds of the invention have high affinity for the
5-HT.sub.1A and D.sub.4 receptors. Accordingly, the compounds of
the invention are considered useful for the treatment of affective
disorders such as general anxiety disorder, panic disorder,
obsessive compulsive disorder, depression, social phobia and eating
disorders; other psychiatric disorders such as psychosis and
neurological disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0039] In preferred embodiments of the invention, Z is O.
[0040] In preferred embodiments of the invention, Y is
--CH.sub.2CH.sub.2-- or --CH.sub.2CO--.
[0041] In preferred embodiments of the invention, X is O or NH.
[0042] In preferred embodiments of the invention, W is N.
[0043] In preferred embodiments of the invention, m is 2.
[0044] In a further embodiment of the invention, n is 2, 3 or
4.
[0045] In a more preferred embodiment of the invention, n is 2.
[0046] In preferred embodiments of the invention, R.sup.1, R.sup.2
and R.sup.3 independently represent hydrogen, halogen or CN.
[0047] In a further embodiment of the invention, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently
selected from a group consisting of hydrogen, heteroaryl,
trifluoromethyl, cyano, C.sub.1-6-alkyl, halogen,
NR.sup.20R.sup.21, SO.sub.2NR.sup.20R.sup.21, aryl,
C.sub.1-6-alkylsulfonyl and carbonylamino.
[0048] In a preferred embodiment of the invention, R.sup.12,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently
selected from hydrogen, thiophen, trifluoromethyl, cyano, methyl,
ethyl, cyclopropyl, chloro, bromo, fluoro, piperazine,
1-piperazine-4-methyl, 1-piperidine, 1-piperidinyl-sulfonyl,
methanesulfonyl, methylsulfid, phenyl and carbonylamino.
[0049] Specific compounds of the invention are compounds selected
from:
[0050]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-6-methylnicotinonitrile, 1a
[0051]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-6-methyl-4-trifluoromethylnicotinonitrile, 1b
[0052]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-6-methyl-4-trifluoromethylnicotinonitrile, 1 c
[0053]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile, 1d
[0054]
{2-[4(8-Cyano-2,3-dihydrobenzo[1,4]dioin-5-yl)piperazin-1yl]ethylsu-
lfanyl}-6-methylnicotinonitrile, 1e
[0055]
3-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-2--
methylpyridine, 1f
[0056]
2-Chloro-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thoxy}pyridine, 1g
[0057]
2-Bromo-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hoxy}pyridine, 1h
[0058]
3-Chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thoxy}pyridine, 1i
[0059]
2-Chloro-3-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethoxy}pyridine, 1j
[0060]
2-Bromo-3-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethoxy}pyridine, 1k
[0061]
3-Chloro-5-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethoxy}pyridine, 1l
[0062]
3-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hoxy}-2-methylpyridine, 1m
[0063]
4-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-3-(piperidin-1-ylsulfonyl)pyridine, 1n
[0064]
4-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-3-(piperidin-1-ylsulfonyl)pyridine, 1o
[0065]
2-{4-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfa-
nyl}-5-trifluoromethylpyridine, 1p
[0066]
2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]bu-
tylsulfanyl}-5-trifluoromethylpyridine, 1q
[0067]
2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]bu-
tylsulfanyl}-5-trifluoromethylpyridine, 1r
[0068]
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulf-
anyl}-5-trifluoromethylpyridine, 1s
[0069]
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulf-
anyl}4,6-dimethylnicotinonitrile, 1t
[0070]
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfa-
nyl}-4,6-dimethylnicotinonitrile, 1u
[0071]
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]pr-
opylslfanyl}-5-trifluoromethylpyridine, 1v
[0072]
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]pr-
opylsulfanyl}-4,6-dimethylnicotinonitrile, 1x
[0073]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}nicotinonitrile, 2a
[0074]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2b
[0075]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}4 methyl-6-(piperidin-1-yl)nicotinonitrile, 2c
[0076]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-6-methylnicotinamide, 2d
[0077]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}nicotinonitrile, 2e
[0078]
4-Cyano-2-{2-[4(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]eth-
oxy}pyridine, 2f
[0079]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-6--
methylnicotinamide, 2g
[0080]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4--
methyl-6-(piperidin-1-yl)nicotinonitrile, 2h
[0081]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4--
methyl-6-(4-methylpiperazin-1-yl)nicotinonitrile, 2i
[0082]
6-Cyclopropyl-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-
-yl]ethoxy)-4-trifluoromethylnicotinonitrile, 2j
[0083]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-3--
methanesulfonyl-4-methyl-6-phenylpyridine, 2k
[0084]
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4,6-dimethyl-3-phenylsulfonylpyridine, 2l
[0085]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}pyridine, 2m
[0086]
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4,6-dimethylnicotinonitrile, 2n
[0087]
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl} methylnicotinonitrile, 2o
[0088]
5-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl}nicotinonitrile, 2p
[0089]
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl}nicotinonitrile, 2q
[0090]
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl}-5-fluoronicotinonitrile, 2r
[0091]
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-4,6-dimethylnicotinonitrile, 2s
[0092]
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-4-methylnicotinonitrile, 2t
[0093]
5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile, 2u
[0094]
5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}nicotinonitrile, 2v
[0095]
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}nicotinonitrile, 2x
[0096]
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2y
[0097]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1--
yl]ethylsulfanyl]nicotinonitrile, 2z
[0098]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1--
yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2aa
[0099]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2ab
[0100]
4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ac
[0101]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2ad
[0102]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]nicotinonitrile, 2ae
[0103]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]nicotinonitrile, 2af
[0104]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-5-fluoronicotinonitrile, 2ag
[0105]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]et-
hylsulfanyl]nicotinonitrile, 2ah
[0106]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]et-
hylsulfanyl]-4,6-dimethylnicotinonitrile, 2ai
[0107]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2aj
[0108]
4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ak
[0109]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2al
[0110]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]nicotinonitrile, 2am
[0111]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]nicotinonitrile, 2an
[0112]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-5-fluoronicotinonitrile, 2ao
[0113]
5-Cyano-4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}pyrimidine, 2ap
[0114]
5-Cyano-4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2aq
[0115]
5-Cyano-4-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethylsulfanyl}pyrimidine, 2ar
[0116]
5-Cyano-4-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2 as
[0117]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4,6-dimethylpyrimidine, 2 at
[0118]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-4,6-dimethylpyrimidine, 2au
[0119]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl} 4-methoxynicotinonitrile, 2av
[0120]
6-Chloro-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl}-5-fluoronicotinonitrile, 2ax
[0121]
6-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2ay
[0122]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-5-ethylpyrimidine, 2az
[0123]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4-trifuoromethylpyrimidine, 2ba
[0124]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4,6-dimethoxypyrimidine, 2bb
[0125]
4-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-6-methylpyrimidine, 2bc
[0126]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-4-trifluoromethylpyrimidine, 2bd
[0127] Some of the compounds of general Formula I may exist as
optical isomers thereof and such optical isomers are also embraced
by the invention.
[0128] The term C.sub.1-6 alkyl refers to a branched or unbranched
alkyl group having from one to six carbon atoms inclusive, such as
methyl, ethyl 1-propyl, 2-propyl, 1-butyl, 2-butyl,
2-methyl-2-propyl and 2-methyl-1-propyl.
[0129] Similarly, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl,
respectively, designate such groups having from two to six carbon
atoms inclusive.
[0130] Halogen means fluoro, chloro, bromo or iodo.
[0131] The term C.sub.3-8 cycloalkyl designates a monocyclic or
bicyclic carbocycle having three to eight C-atoms, such as
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl.
[0132] The terms C.sub.1-6 alkoxy, C.sub.1alkylthio and C.sub.1-6
alkylsulphonyl designate such groups in which the alkyl group is
C.sub.1-6 alkyl as defined above.
[0133] The term aryl designates an aromatic hydrocarbon such as
phenyl or naphtyl.
[0134] The term heteroaryl refers to a mono- or bicyclic
heterocyclic aromatic group containing at least one N, S or O atom,
such as furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, pyridyl, pyrimidyl, tetraaolyl,
benzofuranyl, benzothienyl, benzimidazolyl, indolyl. Preferred
heteroaryls are monocyclic aryls. Especially preferred are thienyl
and piperidinyl.
[0135] Acyl means --CO-alkyl wherein the alkyl group is C.sub.1-6
alkyl as defined above.
[0136] Amino means NH.sub.2.
[0137] C.sub.1-6 alkylamino means --NH-alkyl and
di(C.sub.1-6-alkyl)amino means --N-(alkyl).sub.2 where the alkyl
group is C.sub.1-6 alkyl as defined above.
[0138] Acylamino means --NH-acyl wherein acyl is as defined
above.
[0139] Carbonylamino means --CONH--
[0140] C.sub.1-6 alkoxycarbonylamino means alkyl-O--CO--NH--
wherein the alkyl group is C.sub.1-6 alkyl as defined above.
[0141] C.sub.1-6 alkylaminocarbonylamino means alkyl-NH--CO--NH--
wherein the alkyl group is C.sub.1-6 alkyl as defined above.
[0142] di(C.sub.1-6-alkyl)aminocarbonylamino means
(alkyl).sub.2--N--CO--N- H-- wherein the alkyl group is C.sub.1-6
alkyl as defined above.
[0143] As used herein, a phenyl group which may be substituted
means a phenyl group which may be substituted one or more times
with a substituent selected form halogen, trifluoromethyl, cyano,
nitro, amino, C.sub.1-6-ylamino, di(C.sub.1-6-alkyl)amino,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy and hydroxy.
[0144] Exemplary of organic acid addition salts according to the
invention are those with maleic, fumaric, benzoic, ascorbic,
succinic, oxalic, bis-methylenesalicylic, methanesulfonic,
ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,
gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,
stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,
benzenesulfonic, and theophylline acetic acids, as well as the
8-halotheophyllines, for example 8-bromotheophylline. Exemplary of
inorganic acid addition salts according to the invention are those
with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and
nitric acids. The acid addition salts of the invention are
preferably pharmaceutically acceptable salts formed with non-toxic
acids.
[0145] Furthermore, the compounds of this invention may exist in
unsolvated as well as in solvated forms with pharmaceutically
acceptable solvents such as water, ethanol and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of this invention.
[0146] Some of the compounds of the present invention contain
chiral centres and such compounds exist in the form of isomers
(e.g. enantiomers). The invention includes all such isomers and any
mixtures thereof including racemic mixtures.
[0147] Racemic forms can be resolved into the optical antipodes by
known methods, for example, by separation of diastereomeric salts
thereof with an optically active acid, and liberating the optically
active amine compound by treatment with a base. Another method for
resolving racemates into the optical antipodes is based upon
chromatography on an optically active matrix. Racemic compounds of
the present invention can thus be resolved into their optical
antipodes, e.g., by fractional crystalfisation of d- or
1-(tartrates, mandelates or camphorsulphonate) salts for example.
The compounds of the present invention may also be resolved by the
formation of diastereomeric derivatives.
[0148] Additional methods for the resolution of optical isomers,
known to those skilled in the art, may be used. Such methods
include those discussed by J. Jaques, A. Collet and S. Wilen in
"Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New
York (1981).
[0149] Optically active compounds can also be prepared from
optically active starting materials.
[0150] The compounds of the invention can be prepared by one of the
following methods comprising
[0151] a) treating a compound of formula (II) with a compound of
formula (III) in the presence of a reducing agent. 3
[0152] wherein n, m, R.sup.1-R.sup.3, R.sup.10, R.sup.11,
R.sup.12-R.sup.15, W, X, Y, Z, A and the dotted line are as defined
above;
[0153] b) treating a compound of formula (IV) with a compound of
formula (V) in the presence of an appropriate base 4
[0154] wherein L is a suitable leaving group such as e.g. chloro
and n, m, R.sup.1-R.sup.3, R.sup.10, R.sup.11, R.sup.12R.sup.15, Q,
W, X, Y, Z, A and the dotted line are as defined above;
[0155] Whereupon the compounds of formula (I) are isolated as the
free base or in the form of a pharmaceutically acceptable salt
thereof.
[0156] The reductive amination according to method a) is preferably
carried out in an inert organic solvent such as dimethylformamide
or tetrahydrofuran in the presence of a reducing agent, eg
triacetoxyborohydride, at room temperature.
[0157] The arylation according to method b) is conveniently
performed in an inert organic solvent such as dimethylformamide in
the presence of a base (eg potassium tert-butoxide) at a
temperature in the range of 40-100.degree. C., preferably in the
range of 40-80.degree. C., and most preffered around 50.degree.
C.
[0158] Arylpiperazine derivatives of formula (II) are either
commercially available or conveniently prepared from the
corresponding arylamine according to the method described by Martin
et al. J. Med. Chem. 1989, 32, 1052, or the method described by
Kruse et al. Rec. Trav. Chim. Pays-Bas 1988, 107, 303. The starting
arylamines are either commercially available or are well-described
in the literature.
[0159] Aryltetrahydropyridine derivatives of formula (II) are known
from literature, cf. U.S. Pat. No. 2,891,066; McElvain et al. J.
Amer. Chem. Soc. 1959, 72, 3134. Conveniently, the corresponding
arylbromide is lithiated with BuLi followed by addition of
1-benzyl-4-piperidone. Subsequent treatment with acid gives the
N-benzyl-aryltetrahydropyridine. The benzyl group can be removed by
catalytic hydrogenation or by treatment with e.g. ethyl
chloroformate to give the corresponding ethyl carbamate followed by
acidic or alkaline hydrolysis. The starting arylbromides are either
commercially available or well-described in the literature.
[0160] Aldehydes of formula (IL) are prepared as described in the
Examples below. The starting chloropyridines are commercially
available or made by methods well-described in the literature
[0161] The following examples will illustrate the invention
further. They are, however, not to be construed as limiting.
EXAMPLES
[0162] Melting points were determined on a Blichi SMP-20 apparatus
and are uncorrected. Analytical LC-MS data were obtained on a PE
Sciex API 150EX instrument equipped with IonSpray source (method D)
or heated nebulizer (APCI, methods A and B) and Shimadzu
LC-8A/SLC-10A LC system. The LC conditions [30.times.4.6 mm YMC
ODS-A with 3.5 .mu.m particle size] were linear gradient elufion
with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to
water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2
mL/min. Purity was determined by integration of the UV trace (254
nm). The retention times Rt are expressed in minutes.
[0163] Mass spectra were obtained by an alternating scan method to
give molecular weight information. The molecular ion, MH+, was
obtained at low orifice voltage (5-20V) and fragmentation at high
orifice voltage (100V).
[0164] Preparative LC-MS-separation was performed on the same
instrument. The LC conditions (50.times.20 mm YMC ODS-A with 5
.mu.m particle size) were linear gradient elution with
water/acetonitrile/trifluoroacetic acid (80:20:0.05) to
water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at
22.7 mL/min. Fraction collection was performed by split-flow MS
detection.
[0165] .sup.1H NMR spectra were recorded at 500.13 MFz on a Bruker
Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250
instrument. Deuterated chloroform (99.8% D) or dimethyl sulfoxide
(99.9% D) were used as solvents. TMS was used as internal reference
standard. Chemical shift values are expressed in ppm-values. The
following abbreviations are used for multiplicity of NMR signals:
s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet,
dd=double doublet, dt=double triplet, dq=double quartet, t=triplet
of triplets, m=multiplet, b=broad singlet. NMR signals
corresponding to acidic protons are generally omitted. Content of
water in crystalline compounds was determined by Karl Fischer
titration. Standard workup procedures refer to extraction with the
indicated organic solvent from proper aqueous solutions, drying of
combined organic extracts (anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4), filtering and evaporation of the solvent in
vacuo. For column chromatography silica gel of type Kieselgel 60,
230400 mesh ASTM was used. For ion-exchange chromatography (SCX 1
g, Varian Mega Bond Elut.RTM., Chrompack cat. no. 220776). Prior
use the SCX-columns were preconditioned with 10% solution of acetic
acid in methanol (3 mL).
Example 1
[0166] 4,6-Dimethyl-2-(2-oxoethylsulfanyl)nicotinonitrile.
[0167] 4,6-Dimethyl-2-mercaptonicotinonitrile (3.0 g) was dissolved
in DMF (40 mL) and a solution of potassium tert-butoxide (19.2 mL;
1 M) in tert-butanol added. The mixture was stirred for 10 min,
added dropwise to a solution of bromoacetaldehyd dimethylacetal
(3.2 g) in DMF (10 ml) and stirred over night at 70.degree. C. The
mixture was poured on water and extracted with ethyl acetate, the
combined organic phases dried and evaporated to give an oil (5.3 g)
which was dissolved in dioxane (40 mL). HCl (20 mL; 3 M) was added
and the mixture was stirred at 30.degree. C. for 2 h. NaHCO.sub.3
was added until pH reached 5-6, the mixture was extracted with
ethyl acetate, the combined organic phases dried with
Na.sub.2SO.sub.4 and evaporated to give the title compound as an
oil (2.9 g). .sup.1H NMR (CDCl.sub.3): .delta. 2.45 (s, 6H); 3.35
(d, 2H); 6.85 (s, 1H); 9.55 (t, 1H).
[0168]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-6-methylnicotinonitrile, 1a
[0169] 4,6-Dimethyl-2-(2-oxo-ethylsulfanyl)nicotinonitrile (2.9 g)
was dissolved in 1,2-dichloroethane (150 mL), a solution of
4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazine (2.6 g) in DMF (150
mL) was added, followed by addition of sodium triacetoxyborohydride
(14.9 g) and stirring for 2 h. The mixture was poured on water and
Na.sub.2CO.sub.3 added until pH reached 7-8. The mixture was
extracted with ethyl acetate, the combined organic phases dried and
evaporated to give an oil which was subjected to purification by
column chromatography (silica gel; ethyl acetate and heptane)
giving an oil which precipitated as the oxalate salt (0.36 g) from
acetone. LC/MS (m/z) 397 (H+), RT=1.91, purity: 97%.
[0170] The following compounds were prepared analogously:
[0171]
2-(2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-6-methyl-4-trifluoromethylnicotinonitrile, 1b: LC/MS (m/z) 465
(MH+), RT=2.17, purity: 73%.
[0172] 2-{2-[4-(8-Cyano-Z
3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl)-6-methyl-4-trifluoromethylnicotinonitnle, 1c: LC/MS
(m/z) 490 MH+), RT=2.21, purity: 82%.
[0173]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile, 1d: LC/MS
(m/z) 533 (MH+), RT=2.38, purity: 86%.
[0174]
{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethy-
lsulfanyl)-6-methylnicotinonitrile, 1e: LC/MS (m/z) 422 (NH+),
RT=1.95, purity: 98%.
[0175]
3-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-2--
methylpyridine, 1ff: LC/MS (m/z) 356 (MH+), RT=1.04, purity:
97%.
[0176]
2-Chloro-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thoxy}pyridine 1g: LC/MS (m/z) 376 (MH+), RT=1.54, purity: 95%.
[0177]
2-Bromo-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hoxy}pyridine, 1h: LC/MS (m/z) 422 (MH+), RT=1.63, purity: 90%.
[0178]
3-Chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thoxy}pyridine, 1i: LCFMS (m/z) 376 (MH+), RT=1.54, purity:
95%.
[0179]
2-Chloro-3-(2-[4-(8-cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethoxy}pyridine, 1j: LC/MS (m/z) 401 (MH+), RT=1.54, purity:
94%.
[0180]
2-Bromo-3-(2-[4-(8-Cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethoxy}pyridine, 1k: LC/MS (m/z) 445 (MH+), RT=1.63, purity:
92%.
[0181]
3-Chloro-5-(2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethoxy}pyridine, 1l: LC/AS (m/z) 401 (NM+), RT=1.59, purity:
90%.
[0182]
3-(2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hoxy}-2-methylpyridine, 1m: LC/MS (m/z) 381 (N+), RT=1.08, purity:
100%.
[0183]
4-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-3-(piperidin-1-ylsulfonyl)pyridine, 1n: LC/MS (m/z)
530 (ME+), purity: 88%.
[0184]
4-{2-[4-(2,3-Dilzydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulf-
ianyl}-3-(piperidin-1 ylsulfonyl)pyridine, 1o: LC/MS (m/z) 505
(MH+), RT=1.87, purity: 100%.
[0185] 2-{4-[4-(2,3-Dihydrobenzo[1,
4]dioxin-5-yl)piperazin-1-yl]butylsulf-
yanyl)-5-trfluoromethylpyridine, 1p: LC/MS (m/z) 454 (MH+),
RT=2.14, purity: 75%.
[0186] 2-{4-[4-(8-Cyano-Z
3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]bu-
tylsulfanyl}-5-trifluoromethylpyridine, 1q: LC/MS (m/z) 479 (OM+),
RT=2.14, purity: 82%.
[0187]
2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]bu-
tylsulfanyl}-5-trifluoromethylpyridine, 1r: LC/MS (m/z) 464 (MH+),
RT=2.08, purity: 71%.
[0188]
2-(3-[4-(2,3-Dihydrobenzo[1,4]dioxin-S-yl)piperazin-1-yl]propylsufa-
nyl}-5-trifluoromethylpyridine, 1s: LC/MS (m/z) 440 (MH+), RT=2.07,
purity: 98%.
[0189]
2-(3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulf-
anyl}-4,6-dimethyl-nicotinonitrile, 1t: LC/MS (m/z) 425 (MH+),
RT=1.99, purity: 100%.
[0190]
2-(3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1yl]butylsulfan-
yl)-4,6-dimethyl-nicotinonitrile, 1u: LC/MS (m/z) 439 (MH+),
RT=2.05, purity: 82%.
[0191]
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]pr-
opylsulfanyl}-5-trifluoromethylpyridine, 1v: LC/MS (m/z) 465 (MH+),
RT=2.07, purity: 97%.
[0192]
2-(3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]pr-
opylsulfanyl-4,6-dimethylnicotinonitrile, 1x: LC/MS (m/z) 450
(MH+), RT=2.00, purity: 98%.
Example 2
[0193]
2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]-ethylmercapt-
ane.
[0194] 1-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazine (4.5 g) and
thiirane (1.75 g) were dissolved in DMF (200 mL) and refluxed for 1
h. The mixture was evaporated and re-dissolved in THF, dried with
MgSO.sub.4, filtered and evaporated to give an oil which was
subjected to purification by column chromatography (silica gel;
ethyl acetate and heptane) giving the title compound as an oil (2.2
g). MS m/z (%): 261 (MH+, 100%), 202 (100%), 159 (23%).
[0195]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}nicotinonitrle, 2a.
[0196]
2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylmercapta-
ne (2.2 g) was dissolved in a solution of potassium tert-butoxide
(0.81 g) in DMF (25 ml), stirred for 15 min and heated to
50.degree. C. A solution of 2-chloronicotinonitrile (1.91 g) in DMF
(25 mL) was added dropwise and stirring was continued for another 2
h at 50.degree. C. The mixture was evaporated and re-dissolved in
TBF, washed with brine, dried with MgSO.sub.4, filtered and
evaporated to give an oil which was subjected to purification by
column chromatography (silica gel; ethyl acetate, heptane and
triethyl amine) giving the title compound as an oil which
precipitated as the oxalate salt from acetone. (1.45 g). LC/MS
(m/z) 383 (MH+), RT=1.70, purity: 87%.
[0197] The following compounds were prepared analogously:
[0198]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2b: LC/MS
(m/z) 551 (MH+), RT=2.20, purity: 77%.
[0199] 2-{2-[4-(8-Cyano-Z
3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2c: LC/MS
(m/z) 505 (MH+), RT=2.33, purity: 87%.
[0200]
2-{2-[4-(8-Cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-6-methylnicotinamide, 2d: LC/MS (m/z) 440 (MH+),
RT=1.58, purity: 90%.
[0201] 2-{2-[4-(8-Cyano-Z
3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}nicotinonitrile, 2e: LC/MS (m/z) 408 (MH+), RT=1.75,
purity: 96%.
[0202]
4-Cyano-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hoxy}pyridine, 2f: LC/MS (m/z) 367 (MH+), RT=1.62, purity: 82%.
[0203]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-6--
methylnicotinamide, 2g: LC/MS (m/z) 399 (NM+), RT=1.55, purity:
97%.
[0204]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4--
methyl-6-(piperidin-1-yl)nicotinonitrile, 2h: LC/MS (m/z) 464
(MH+), RT=2.24, purity: 98%.
[0205]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4--
methyl-6-(4-methylpiperazin-1-yl)nicotinonitrile, 2i: LC/MS (m/z)
479 (MH+), RT=1.34, purity: 79%.
[0206] 6-Cyclopropyl-2-{2-[4-(2,3-dihydrobenzo[1,
4]dioxin-5-yl)piperazin--
1-yl]ethoxy)-4-trifluoromethylnicotinonitrile, 2j: LC/MS (m/z) 475
(MH+), RT=2.29, purity: 99%.
[0207]
2-{2-[4-(2,3-Dilydrobenzo[1,4]dioxin-5-yl)piperazin-3-yl]ethoxy}-3--
methanesulfonyl-4-methyl-6-phenylpyridine, 2k: LC/MS (m/z) 510
(MH+), RT=2.16, purity: 98%.
[0208] 2-{3-[4-(2,3-Dihydrobenzo[1,
4]dioxin-5-yl)piperazin-1-yl]ethylsulf-
anyl}-4,6-dimethyl-3-phenylsulfonylpyridine, 21: LC/MS (m/z) 526
(NH+), RT=2.11, purity: 92%.
[0209]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}pyridine, 2m: LC/MS (m/z) 383 MH+), RT=1.67, purity:
87%.
[0210]
2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4,6-dimethylnicotinonitrile, 2n: LC/MS (m/z) 412 (MH+),
RT=2.02, purity: 96%.
[0211]
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfyanyl}-4-methylnicotinonitrile, 2o: LC/MS (m/z) 432 (MH+),
RT=2.00, purity: 93%.
[0212]
5-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl}nicotinonitrile, 2p: LC/MS (m/z) 418 (M+), RT=1.90,
purity: 73%.
[0213]
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsuyfanyl}nicotinonitrile, 2q: LC/MS (m/z) 418 (MH+), RT=1.91,
purity: 72%.
[0214]
6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl)}-5-fluoronicotinonitrile, 2r: LC/MS (m/z) 436 (MH+),
RT=1.95, purity: 89%.
[0215]
2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfaityl}-4,6-dimethylnicotinonitrile, 2s: LC/S (m/z) 436
(M}I+), RT=2.04, purity: 78%.
[0216]
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl)-4-methylnicotinonitrile, 2t: LC/MS (m/z) 457
(MH+), RT=2.04, purity: 87%.
[0217] 5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[,
4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile,
2u: LC/MS (m/z) 471 (MH+), RT=2.24, purity: 81%.
[0218]
5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}nicotinonitrile, 2v: LC/MS (m/z) 443 (MH+),
RT=1.97, purity: 81%.
[0219]
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}nicotinonitrile, 2.times.: LC/MS (m/z) 443
(MH+), RT=1.91 purity: 87%.
[0220]
6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2y: LC/MS (m/z) 461
(MH+), RT=1.62, purity: 84%.
[0221] 2-[2-[4-(6-Chloro-Z
3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1--
yl]ethylsulfanyl]nicotinonitrile, 2z: LC/MS (m/z) 431 (MH+),
RT=1.62, purity: 94%.
[0222]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1--
yl]ethylsuyanyl]-4,6-dimethylnicotinonitrile, 2aa: LC[MS (m/z) 459
(MH+), RT=1.87, purity: 72%.
[0223]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2ab: LC/MS
(m/z) 479 (MH+), RT=1.91, purity: 97%.
[0224]
4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ac: LC/MS
(m/z) 479 (MH+), RT=1.87, purity: 85%.
[0225]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2ad: LC/MS
(m/z) 493 MH+), RT=2.12, purity: 98%.
[0226]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]nicotinonitrile, 2ae: LC/MS (m/z) 465
(MH+), RT=1.87, purity: 96%.
[0227]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]nicotinonitrile, 2af: LC/MS (m/z) 465
(MH+), RT=1.79, purity: 98%.
[0228]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)pip-
erazin-1-yl]ethylsulfanyl]-5-fluoronicotinonitrile, 2ag: LC/MS
(m/z) 483 (MH+), RT=1.83, purity: 96%.
[0229]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]et-
hylsurfanyl]nicotinonitrile, 2ah: LC/MS (m/z) 417 (MH+), RT=1.75,
purity: 93%.
[0230]
2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]et-
hylsulfanyl]-4,6-dimethylnicotinonitrile, 2ai: LC/MS (m/z) 445
(MH+), RT=2.04, purity: 96%.
[0231]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2aj: LC/MS (m/z) 465
(MH+), RT=2.08, purity: 96%.
[0232]
4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ak: LC/MS (m/z) 465
(MH+), RT=1.95, purity: 89%.
[0233] 5-Chloro-2-[2-[4-(6-chloro-Z
3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2al: LC/MS (m/z)
479 (NH+), RT=2.24, purity: 97%.
[0234]
5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]nicotinonitrile, 2am: LC/MS (m/z) 451 (MIJ+),
RT=2.00, purity: 96%.
[0235]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]nicotinonitrile, 2an: LC/MS (m/z) 451 (MH+),
RT=1.95, purity: 74%.
[0236]
6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazi-
n-1-yl]ethylsulfanyl]-5-fluoronicotinonitrile, 2ao: LC/MS (m/z) 469
(ME+), RT=2.00, purity: 96%.
[0237]
5-Cyano-4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}pyrimidine, 2ap: LC/MS (m/z) 384 (MH+), RT=1.66,
purity: 99%.
[0238] 5-Cyano-4-{2-[4-(2,3-dihydrobenzo[ ],
4]dioxin-5-yl)piperazin-1-yl]-
ethylsulfanyl)-6-methylsulfanyl-2-phenylpyrimidine, 2aq: LC/MS
(m/z) 507 (MH+), RT=2.49, purity: 93%.
[0239]
5-Cyano-4-(2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethylsuifanyl}pyrimidine, 2ar: LC/MS (m/z) 409 (MH+),
RT=1.70, purity: 98%.
[0240]
5-Cyano-4-(2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-
-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2 as:
LC/MS (m/z) 532 (MH+), RT=2.49, purity: 91%.
[0241]
2-{2-[4-(2,3-Dihydrobenizo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulf-
anyl}4, 6-dimethylpyrimidine, 2 at: LC/MS (m/z) 387 (ME+), RT=1.66,
purity: 95%.
[0242]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-4,6-dimethylpyrimidine, 2au: LC/MS (m/z) 413 (MH+),
RT=1.70, purity: 80%.
[0243]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4-methoxynicotinonitrile: 2av: LC/MS (m/z) 414 (MH+), RT=1.8,
purity: 83%.
[0244]
6-Chloro-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]e-
thylsulfanyl}-5-fluoronicotinonitrile, 2ax: LC/MS (m/z) 436 (MH+),
RT=2.0, purity: 86%.
[0245]
6-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulanyl}-5-fluoronicotinonitrile, 2ay: LC/MS (m/z) 461
(MH+), RT=2.0, purity: 84%.
[0246]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-S-ethylpyrimidine, 2az: LCJAMS (m/z) 387 (MH+), RT=1.8,
purity: 83%.
[0247]
2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfa-
nyl}-4-trifluoromethylpyrimidine, 2ba: LC/MS (m/z) 427 (MH+),
RT=1.8, purity: 78%.
[0248] 2-{2-[4-(2,3-Dihydrobenzo[1,
4]dioxin-5-yl)piperazin-1-yl]ethylsulf-
anyl}-4,6-dimethoxypyrimidine, 2bb: LC/MS (m/z) 420 (NM+), RT=1.9,
purity: 70%.
[0249]
4-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazi-
n-1-yl]ethylsulfanyl}-6-methylpyrimidine, 2bc: LC/MS (m/z) 433
(MH+), RT=1.8, purity: 78%.
[0250]
2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]et-
hylsulfanyl}-4-trifluoromethylpyrimidine, 2bd: LC/MS (m/z) 434
(MH+), RT=2.0, purity: 84%.
[0251] Pharmacological Testing
[0252] The affinity of the compounds of the invention to
5-HT.sub.1A receptors was determined by measuring the inhibition of
binding of a radioactive ligand at 5-HT.sub.1A receptors as
described in the following test:
[0253] Inhibition of .sup.3H-5-CT Binding to Human 5-HT.sub.1A
Receptors.
[0254] By this method the inhibition by drugs of the binding of the
5-HT.sub.1A agonist .sup.3H-5-carboxamido tryptamine (.sup.3H-5-CT)
to cloned human 5-HT.sub.1A receptors stably expressed in
transfected HeLa cells (HA7) (Fargin, A. et al. J. Biol. Chem.
1989, 264, 14848) is determined in vitro. The assay was performed
as a modification of the method described by Harrington, M. A. et
al. J. Pharmacol. Exp. Ther. 1994, 268, 1098. Human 5-HT.sub.1A
receptors (40 .mu.g of cell homogenate) were incubated for 15
minutes at 37.degree. C. in 50 mM Tris buffer at pH 7.7 in the
presence of .sup.3H-5-CT. Non-specific binding was determined by
including 10 .mu.M of metergoline. The reaction was terminated by
rapid filtration through Unifilter GF/B filters on a Tomtec Cell
Harvester. Filters were counted in a Packard Top Counter. Compounds
1a, 1b, 2a, 2c, 2l, 2o, 2s, 2u, 2z, 2aa, 2ah, 2ai and 2aj were
tested and showed IC.sub.50 values of less than 300 nM.
[0255] The compounds of the invention have also been tested for
their effect on re-uptake of serotonin in the following test:
[0256] Inhibition of .sup.3H-5-HT Uptake Into Rat Brain
Synaptosomes.
[0257] Using this method, the ability of drugs to inhibit the
accumulation of .sup.3H-5-HT into whole rat brain synaptosomes is
determined in vitro. The assay was performed as described by
Hyttel, J. Psychopharmacology 1978, 60, 13. Compounds 1a, 1r, 2a,
2c, 21, 2o, 2s, 2u, 2z, 2aa, 2ah, 2ai and 2aj were tested and
showed IC.sub.50 values of less than 20 nM.
[0258] The 5-HT.sub.1A antagonistic activity of some of the
compounds of the invention has been estimated in vitro at cloned
5-HT.sub.1A receptors stably expressed in transfected HeLa cells
(HA7). In this test, 5-HT.sub.1A antagonistic activity is estimated
by measuring the ability of the compounds to antagonize the 5-HT
induced inhibition of forskolin induced cAMP accumulation. The
assay was performed as a modification of the method described by
Pauwels, P. J. et al. Biochem. Pharmacol. 1993, 45, 375. Compounds
1a, 1b, 1e and 1v were tested and showed IC.sub.50 values of less
than 7000 nM.
[0259] Some of the compounds of the invention have also been tested
for their in vivo effect on 5-HT.sub.1A receptors in the assay
described by Sanchez. C. et al. Eur. J. Pharmacol. 1996, 315, pp
245. In this test, antagonistic effects of test compounds are
determined by measuring the ability of the test compounds to
inhibit 5-MeO-DMT induced 5-HT syndrome.
[0260] The compounds of the present invention possess valuable
activity as serotonin re-uptake inhibitors and have antagonistic
effect at 5-HT.sub.1A receptors. The compounds of the invention are
therefore considered useful for the treatment of diseases and
disorders responsive to the inhibition of serotonin re-uptake and
antagonistic activity at 5-HT.sub.1A receptors. Diseases responsive
to the inhibition of serotonin re-uptake are well-known in the art
and include affective disorders, such as depression, psychosis,
anxiety disorders including general anxiety disorder, panic
disorder, obsessive compulsive disorder, etc.
[0261] As explained above, the antagonistic activity at 5-HT.sub.1A
receptors of the compounds of the invention will counteract the
negative feed back mechanism induced by the inhibition of serotonin
reuptake and is thereby expected to improve the effect of the
serotonin reuptake inhibiting activity of the compounds of the
invention.
[0262] The compounds as claimed herein are therefore considered to
be particularly useful as fast onset of action medicaments for the
treatment of depression. The compounds may also be useful for the
treatment of depressions which are non-responsive to currently
available SSRIs.
[0263] Some of the compounds of the invention have also been found
to have affinity to dopamine D.sub.3 and D.sub.4 receptors in the
following two assays.
[0264] Inhibition of the Binding of .sup.3H-YM-09151-2 to Human
Dopamine D.sub.4 Receptors
[0265] By this method, the inhibition by drugs of the binding of
[.sup.3H]YM-09151-2 (0.06 nM) to membranes of human cloned dopamine
D.sub.4.2-receptors expressed in CHO-cells is determined in vitro.
Method modified from NEN Life Science Products, Inc., technical
data certificate PC2533-10/96.
[0266] Inhibition of the Binding of [.sup.3H]Spiperone to Human
D.sub.3 Receptors
[0267] By this method, the inhibition by drugs of the binding
[.sup.3H]Spiperone (0.3 nM) to membranes of human cloned dopamine
D.sub.3-receptors expressed in CHO-cells is determined in vitro.
Method modified from RG. MacKenzie et al. Eur. J. Pharm.-Mol.
Pharm. Sec. 1994, 266, 79-85.
[0268] As seen from the above, the compounds of the invention show
affinity for the 5-HT.sub.1A receptors, inhibitory activity at
serotonin reuptake sites, and affinity for dopamine D.sub.3 and
D.sub.4 receptors. Accordingly, the compounds are considered useful
for the treatment of psychiatric and neurological disorders as
mentioned previously.
[0269] Pharmaceutical Formulation
[0270] The pharmaceutical formulations of the invention may be
prepared by conventional methods in the art. For example: Tablets
may be prepared by mixing the active ingredient with ordinary
adjuvants and/or diluents and subsequently compressing the mixture
in a conventional tabletting machine. Examples of adjuvants or
diluents comprise: corn starch, potato starch, talcum, magnesium
stearate, gelatine, lactose, gums, and the like. Any other
adjuvants or additives usually used for such purposes such as
colourings, flavourings, preservatives etc. may be used provided
that they are compatible with the active ingredients. Solutions for
injections may be prepared by dissolving the active ingredient and
possible additives in a part of the solvent for injection,
preferably sterile water, adjusting the solution to desired volume,
sterilising the solution and filling it in suitable ampules or
vials. Any suitable additive conventionally used in the art may be
added, such as tonicity agents, preservatives, antioxidants,
etc.
[0271] The pharmaceutical compositions of this invention or those
which are manufactured in accordance with this invention may be
administered by any suitable route, for example orally in the form
of tablets, capsules, powders, syrups, etc., or parenterally in the
form of solutions for injection. For preparing such compositions,
methods well-known in the art may be used, and any pharmaceutically
acceptable carriers, diluents, excipients or other additives
normally used in the art may be used.
[0272] Conveniently, the compounds of the invention are
administered in unit dosage form containing said compounds in an
amount of about 0.01 to 1000 mg. The total daily dose is usually in
the range of about 0.05-500 mg, and most preferably about 0.1 to 50
mg of the active compound of the invention.
* * * * *