Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-20
2004-07-27
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S403000, C514S415000, C514S370000, C514S314000, C514S217080, C514S217050, C514S323000, C546S113000, C546S172000, C546S119000, C546S201000, C548S362500, C548S361100, C548S466000, C548S181000, C540S599000, C540S602000, C540S603000
Reexamination Certificate
active
06767912
ABSTRACT:
BACKGROUND OF THE INVENTION
A number of central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues.
The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Compounds which interact with, stimulate or inhibit the 5-HT6 receptor are commonly referred to as 5-HT6 ligands. These 5-HT6 receptor ligands are believed to be of potential use in the treatment of a variety of central nervous system disorders such as anxiety, depression, epilepsy, obsessive-compulsive disorders, migraine, cognitive disorders, sleep disorders, feeding disorders, panic attacks, disorders relating to withdrawl from drug abuse, schizophrenia, or the like or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I wherein
Q is SO
2
, CO, CONR
24
, CSNR
25
or CH
2
;
W is N or CR
6
;
X is N or CR
7
;
Y is NR
8
or CR
9
R
10
;
n is 0 or an integer of 1 or 2;
Z is NR
11
or CR
12
R
13
with the proviso that when n is 1, Q is SO
2
CO or CH
2
, and W is CR
6
then Z must be CR
12
R
13
and with the further provisos that when Y is NR8 then Z must be CR
12
R
13
and at least one of Y and Z must be NR8 or NR
11
;
R
1
, R
2
and R
7
are each independently H, halogen, CN, OCO
2
HR
14
, CO
2
R
15
, CONR
29
R
30
, CNR
16
NR
17
R
18
, SO
m
R
19
, NR
20
R
21
, OR
22
, COR
23
or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R
3
, R
4
, R
9
, R
10
, R
12
and R
13
are each independently H or an optionally substituted C
1
-C
6
alkyl group;
R
5
is an optionally substituted C
1
-C
6
alkyl, aryl or heteroaryl group;
m is 0 or an integer of 1 or 2;
R
6
is H, halogen, or an optionally substituted C
1
-C
6
alkyl, C
1
-C
6
alkoxy, aryl or heteroaryl group;
R
8
and R
11
are each independently H, CNR
26
NR
27
R
28
or a C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;
R
14
, R
15
, R
22
and R
23
are each independently H or an optionally substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R
16
, R
17
, R
18
, R
20
, R
20
, R
26
, R
27
, R
28
, R
29
and R
30
are each independently H or C
1
-C
4
alkyl;
R
19
is an optionally substituted C
1
-C
6
alkyl, aryl or heteroaryl group;
R
24
and R
25
are each independently H or an optionally substituted C
1
-C
6
alkyl, aryl or heteroaryl group; and
----
represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention further provides methods and compositions useful for the treatment of central nervous system disorders affected by or related to the 5-HT6 receptor.
DETAILED DESCRIPTION OF THE INVENTION
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
Surprisingly, it has now been found that heterocyclylindazole or -azaindazole compounds of formula I demonstrate affinity for the 5-HT6 receptor along with significant receptor sub-type selectivity. Advantageously, said formula I compounds are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides heterocyclylindazole or -azaindazole compounds of formula I
wherein
Q is SO
2
, CO, CONR
24
, CSNR
25
or CH
2
;
W is N or CR
6
;
X is N or CR
7
;
Y is NR
8
or CR
9
R
10
;
n is 0 or an integer of 1 or 2;
Z is NR
11
or CR
12
R
13
with the proviso that when n is 1, Q is SO
2
, CO or CH
2
, and W is CR
6
then Z must be CR
12
R
13
and with the further provisos that when Y is NR
8
then Z must be CR
12
R
13
and at least one of Y and Z must be NR
8
or NR
11
;
R
1
, R
2
and R
7
are each independently H, halogen, CN, OCO
2
R
14
, CO
2
R
15
, CONR
29
R
30
, CNR
16
NR
17
R
18
, SO
m
R
19
, NR
20
R
21
, OR
22
, COR
23
or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R
3
, R
4
, R
9
, R
10
, R
12
and R
13
are each independently H or an optionally substituted C
1
-C
6
alkyl group;
R
5
is an optionally substituted C
1
-C
6
alkyl, aryl or heteroaryl group;
m is 0 or an integer of 1 or 2;
R
6
is H, halogen, or an optionally substituted C
1
-C
6
alkyl, C
1
-C
6
alkoxy, aryl or heteroaryl group;
R
8
and R
11
are each independently H, CNR
26
NR
27
R
28
or a C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;
R
14
, R
15
, R
22
and R
23
are each independently H or an optionally substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R
16
, R
17
, R
18
, R
20
, R
21
, R
26
, R
27
, R
28
, R
29
, and R
30
are each independently H or C
1
-C
4
alkyl;
R
19
is an optionally substituted C
1
-C
6
alkyl, aryl or heteroaryl group;
R
24
and R
25
are each independently H or an optionally substituted C
1
-C
6
alkyl, aryl or heteroaryl group; and
----
represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F; the term aryl designates phenyl or n
Cole Derek Cecil
Kelly Michael Gerard
Lennox William Joseph
Zhou Ping
Huang Evelyn Mei
Lences Barbara L.
Wyeth
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